Paul Hollenberg

Summary

Affiliation: University of Michigan
Country: USA

Publications

  1. ncbi Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications
    Paul F Hollenberg
    Department of Pharmacology, University of Michigan, Medical Science Research Building III, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 21:189-205. 2008
  2. pmc Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 5632, USA
    Drug Metab Dispos 39:345-50. 2011
  3. pmc The Inactivation of Human CYP2E1 by Phenethyl Isothiocyanate, a Naturally Occurring Chemopreventive Agent, and Its Oxidative Bioactivation
    Yasushi Yoshigae
    Department of Pharmacology, 2301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109 5632
    Drug Metab Dispos 41:858-69. 2013
  4. pmc Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism
    Cesar Kenaan
    Chemical Biology Doctoral Program, The University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 41:101-10. 2013
  5. pmc Bioactivation of the cancer chemopreventive agent tamoxifen to quinone methides by cytochrome P4502B6 and identification of the modified residue on the apoprotein
    Chitra Sridar
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 40:2280-8. 2012
  6. pmc Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts
    Chitra Sridar
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI, USA
    Drug Metab Dispos 40:2256-66. 2012
  7. pmc Mechanism-based inactivation of cytochrome P450 2B6 by methadone through destruction of prosthetic heme
    Hemali T Amunugama
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 40:1765-70. 2012
  8. pmc Identification of the residue in human CYP3A4 that is covalently modified by bergamottin and the reactive intermediate that contributes to the grapefruit juice effect
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    Drug Metab Dispos 40:998-1006. 2012
  9. ncbi Mechanistic studies with N-benzyl-1-aminobenzotriazole-inactivated CYP2B1: differential effects on the metabolism of 7-ethoxy-4-(trifluoromethyl)coumarin, testosterone, and benzphetamine
    Ute M Kent
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Arch Biochem Biophys 423:277-87. 2004
  10. pmc Thr302 is the site for the covalent modification of human cytochrome P450 2B6 leading to mechanism-based inactivation by tert-butylphenylacetylene
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 39:2431-9. 2011

Research Grants

  1. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2009
  2. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2007
  3. INTERDEPARTMENTAL TRAINING IN PHARMACOLOGICAL SCIENCES
    Paul Hollenberg; Fiscal Year: 2007
  4. Hemeprotein--Catalyzed Oxygenerations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2005
  5. HEMEPROTEIN--CATALYZED OXYGENATIONS OF CARCINOGENS
    Paul Hollenberg; Fiscal Year: 2000
  6. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul F Hollenberg; Fiscal Year: 2010

Collaborators

  • Natasha T Snider
  • J M Rae
  • Danni L Harris
  • David Ballou
  • Yoichi Osawa
  • William W Johnson
  • Shinichiro Hanada
  • Xinxin Ding
  • Yoshihiro Morishima
  • Theunis C Goosen
  • WILLIAM PRATT
  • M Aviram
  • J Andrew Williams
  • Elizabeth M J Gillam
  • Hsia lien Lin
  • Ute M Kent
  • Haoming Zhang
  • Chitra Sridar
  • Linda B von Weymarn
  • Namandjé N Bumpus
  • Cesar Kenaan
  • Anna L Blobaum
  • Mohamad Shebley
  • Lucy Waskell
  • Djemel Hamdane
  • Yoshimasa Kobayashi
  • Yasushi Yoshigae
  • Matthew J Pratt-Hyatt
  • Hemali T Amunugama
  • Erin Harleton
  • Monica I Jushchyshyn
  • Hemali Amunugama
  • William L Alworth
  • Kathleen R Noon
  • Edith J Mensah-Osman
  • Jamie A Chun
  • John M Rimoldi
  • Satish G Puppali
  • Laurence H Baker
  • Dafydd G Thomas
  • Thomas J Giordano
  • Danielle E Mills
  • Hassan R Dhaini
  • Jennifer L Vuletich
  • Erin V Shea
  • Jaime D'Agostino
  • Christine Medower
  • Nyemade Cooper
  • Sarah Ney
  • Monica Jushchyshyn
  • Gaston Hui Bon Hoa
  • Vyvyca J Walker
  • Kate Noon
  • Bill Alworth
  • Greg Spahlinger
  • Alecia McCall
  • Maryam Foroozesh
  • Gabriel A Knudsen
  • Dennis P Hughes
  • Michelle M Tabb
  • Michelle L Lizyness
  • Jose M Larios
  • Eugene Myshkin
  • Bruce Blumberg
  • Kelly A Regal
  • Holly Brevig
  • Qing Yu Zhang
  • Rebecca A Roof
  • Shaomeng Wang
  • Marie Webster
  • Lise Pascual
  • Yipin Lu
  • J Sybil Biermann
  • Timothy D Johnson
  • Kirsten Leu
  • Rajendram V Rajnarayanan
  • Mira Rosenblat
  • Lisa M Notley
  • Suree Jianmongkol
  • Yasuhiko Kamada
  • Ezra R Lowe
  • Andrew T Bender
  • Damon R Demady

Detail Information

Publications66

  1. ncbi Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications
    Paul F Hollenberg
    Department of Pharmacology, University of Michigan, Medical Science Research Building III, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 21:189-205. 2008
    ..The clinical significance of inactivating human P450s for improving drug efficacy as well as drug safety is discussed along with the potential for exploiting mechanism-based inactivators of P450s for therapeutic benefits...
  2. pmc Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 5632, USA
    Drug Metab Dispos 39:345-50. 2011
    ..Because OSI-930 is an inactivator of P450 3A4 but does not exhibit any effect on P450 3A5 activity under the same conditions, it may be an appropriate probe for exploring unique aspects of these two very similar P450s...
  3. pmc The Inactivation of Human CYP2E1 by Phenethyl Isothiocyanate, a Naturally Occurring Chemopreventive Agent, and Its Oxidative Bioactivation
    Yasushi Yoshigae
    Department of Pharmacology, 2301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109 5632
    Drug Metab Dispos 41:858-69. 2013
    ..Digestion of the inactivated enzyme and analysis by SEQUEST showed that Cys 268 may be the residue modified by PIC...
  4. pmc Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism
    Cesar Kenaan
    Chemical Biology Doctoral Program, The University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 41:101-10. 2013
    ....
  5. pmc Bioactivation of the cancer chemopreventive agent tamoxifen to quinone methides by cytochrome P4502B6 and identification of the modified residue on the apoprotein
    Chitra Sridar
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 40:2280-8. 2012
    ..This revealed a tryptic peptide ¹⁸⁸FHYQDQE¹⁹⁴ with the site of adduct formation localized to Gln193 as the site modified by the reactive metabolite formed during tamoxifen metabolism...
  6. pmc Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts
    Chitra Sridar
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI, USA
    Drug Metab Dispos 40:2256-66. 2012
    ....
  7. pmc Mechanism-based inactivation of cytochrome P450 2B6 by methadone through destruction of prosthetic heme
    Hemali T Amunugama
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 40:1765-70. 2012
    ..The evidence strongly suggests that destruction of prosthetic heme is the underlying mechanism leading to the inactivation of CYP2B6 by methadone...
  8. pmc Identification of the residue in human CYP3A4 that is covalently modified by bergamottin and the reactive intermediate that contributes to the grapefruit juice effect
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    Drug Metab Dispos 40:998-1006. 2012
    ..In conclusion, we have determined that the reactive intermediate, oxygenated DHBG, covalently binds to Gln273 and thereby contributes to the mechanism-based inactivation of CYP3A4 by BG...
  9. ncbi Mechanistic studies with N-benzyl-1-aminobenzotriazole-inactivated CYP2B1: differential effects on the metabolism of 7-ethoxy-4-(trifluoromethyl)coumarin, testosterone, and benzphetamine
    Ute M Kent
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Arch Biochem Biophys 423:277-87. 2004
    ....
  10. pmc Thr302 is the site for the covalent modification of human cytochrome P450 2B6 leading to mechanism-based inactivation by tert-butylphenylacetylene
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 39:2431-9. 2011
    ..In conclusion, Thr302 of CYP2B6 is covalently modified by a reactive metabolite of BPA, and this modification is responsible for the mechanism-based inactivation...
  11. pmc Investigation of the mechanisms underlying the differential effects of the K262R mutation of P450 2B6 on catalytic activity
    Namandjé N Bumpus
    Department of Pharmacology, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    Mol Pharmacol 74:990-9. 2008
    ..It is therefore proposed that the oxyferrous or iron-peroxo intermediate formed by the mutant enzyme in the presence of 17EE and efavirenz may be less stable than the same intermediates formed by the wild-type enzyme...
  12. ncbi The grapefruit juice effect is not limited to cytochrome P450 (P450) 3A4: evidence for bergamottin-dependent inactivation, heme destruction, and covalent binding to protein in P450s 2B6 and 3A5
    Hsia lien Lin
    Department of Pharmacology, 2301 MSRBIII, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 313:154-64. 2005
    ..Two of metabolites were identified as 6',7'-dihydroxybergamottin and bergaptol...
  13. ncbi Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 0632, USA
    J Pharmacol Exp Ther 301:160-7. 2002
    ....
  14. ncbi Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6
    Chitra Sridar
    Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 301:945-52. 2002
    ..Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity...
  15. ncbi Metabolism of N,N',N"-triethylenethiophosphoramide by CYP2B1 and CYP2B6 results in the inactivation of both isoforms by two distinct mechanisms
    Erin Harleton
    Department of Pharmacology, Medical Science Research Building III, 1150 West Medical Center Dr, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 310:1011-9. 2004
    ..The data indicate that tTEPA metabolism by these two 2B isoforms results in inactivation of the P450s by two distinct mechanisms...
  16. ncbi Regulation of cytochrome P450 2E1 by heat shock protein 90-dependent stabilization and CHIP-dependent proteasomal degradation
    Yoshihiro Morishima
    Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109 0632, USA
    Biochemistry 44:16333-40. 2005
    ..Our observations lead to a general model of how substrates, such as ethanol, can regulate the interaction of CYP2E1 with the chaperones hsp90 and hsp70 to profoundly alter enzyme turnover...
  17. pmc Metabolic activation of mifepristone [RU486; 17beta-hydroxy-11beta-(4-dimethylaminophenyl)-17alpha-(1-propynyl)-estra-4,9-dien-3-one] by mammalian cytochromes P450 and the mechanism-based inactivation of human CYP2B6
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 5632, USA
    J Pharmacol Exp Ther 329:26-37. 2009
    ..It seems that the potential for drug-drug interactions of RU486 may not be limited only to CYP3A4 and should also be evaluated for drugs metabolized primarily by CYP2B6, such as bupropion and efavirenz...
  18. pmc Identification of 17-alpha-ethynylestradiol-modified active site peptides and glutathione conjugates formed during metabolism and inactivation of P450s 2B1 and 2B6
    Ute M Kent
    Department of Pharmacology, The University of Michigan, Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 19:279-87. 2006
    ....
  19. pmc Modification of serine 360 by a reactive intermediate of 17-alpha-ethynylestradiol results in mechanism-based inactivation of cytochrome P450s 2B1 and 2B6
    Ute M Kent
    Department of Pharmacology, University of Michigan, Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 21:1956-63. 2008
    ..These results suggest that the inactivation by 17EE may be due to modification of an amino acid residue in the substrate access channel near the point of entry into the active site...
  20. ncbi Synthesis of substituted phenyl diaziridines and characterization as mechanism-based inactivators of human cytochrome P450 2B6
    Chitra Sridar
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 34:1849-55. 2006
    ..Binding spectra suggest that this compound bound reversibly to P450 2B6, and preliminary results indicate that 3-(4-methylthiophenyl)-3-(trifluoromethyl)diaziridine is metabolized by P450 2B6...
  21. ncbi Mutation of a single residue (K262R) in P450 2B6 leads to loss of mechanism-based inactivation by phencyclidine
    Mohamad Shebley
    Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 35:1365-71. 2007
    ..These data suggest that the lysine 262 residue plays an important role in the formation of a reactive intermediate of PCP that leads to the mechanism-based inactivation of P450 2B6...
  22. ncbi Effect of 17-alpha-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes: characterization of inactivation of P450s 2B1 and 2B6 and identification of metabolites
    Ute M Kent
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
    J Pharmacol Exp Ther 300:549-58. 2002
    ..Analysis of the 17EE metabolites showed that 2B enzymes that become inactivated differ primarily by their ability to generate two metabolites that were not produced by P450s 2B2 or 2B4...
  23. ncbi Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases
    Chitra Sridar
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109, USA
    Drug Metab Dispos 32:587-94. 2004
    ..Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown...
  24. ncbi Selective pathways for the metabolism of phencyclidine by cytochrome p450 2b enzymes: identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts
    Mohamad Shebley
    Department of Pharmacology, The University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 34:375-83. 2006
    ..These data suggest that P450 2B6 favors oxidation pathways for PCP metabolism that are different from those of P450s 2B1 and 2B4...
  25. pmc Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications
    Natasha T Snider
    Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, 7720 Medical Science II, 1301 E Catherine Street, Ann Arbor, MI 48109 5622, USA
    Pharmacol Rev 62:136-54. 2010
    ....
  26. ncbi Mechanism-based inactivation of cytochromes P450 2E1 and 2E1 T303A by tert-butyl acetylenes: characterization of reactive intermediate adducts to the heme and apoprotein
    Anna L Blobaum
    Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 15:1561-71. 2002
    ....
  27. ncbi Peroxynitrite inactivation of human cytochrome P450s 2B6 and 2E1: heme modification and site-specific nitrotyrosine formation
    Hsia lien Lin
    Department of Pharmacology, University of Michigan and VA Medical Center, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 20:1612-22. 2007
    ....
  28. ncbi Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation
    Linda B von Weymarn
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Chem Res Toxicol 20:1252-9. 2007
    ..The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies...
  29. ncbi Anandamide metabolism by human liver and kidney microsomal cytochrome p450 enzymes to form hydroxyeicosatetraenoic and epoxyeicosatrienoic acid ethanolamides
    Natasha T Snider
    Department of Pharmacology, University of Michigan, 2301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109 0632, USA
    J Pharmacol Exp Ther 321:590-7. 2007
    ..The in vivo formation and biological relevance of the P450-derived HETE and EET ethanolamides remains to be determined...
  30. ncbi Structure-activity relationship and elucidation of the determinant factor(s) responsible for the mechanism-based inactivation of cytochrome P450 2B6 by substituted phenyl diaziridines
    Yoshimasa Kobayashi
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 34:2102-10. 2006
    ....
  31. ncbi Threonine-205 in the F helix of p450 2B1 contributes to androgen 16 beta-hydroxylation activity and mechanism-based inactivation
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 0632, USA
    J Pharmacol Exp Ther 306:744-51. 2003
    ..Our results demonstrate the importance of Thr-205 in determining substrate specificity and product formation as well as in influencing the susceptibility of p450 2B1 to mechanism-based inactivators...
  32. pmc Mechanistic analysis of the inactivation of cytochrome P450 2B6 by phencyclidine: effects on substrate binding, electron transfer, and uncoupling
    Mohamad Shebley
    Department of Pharmacology, The University of Michigan, Medical Science Research Building III, 1150 W Medical Center Drive, Ann Arbor, MI 48109 5632, USA
    Drug Metab Dispos 37:745-52. 2009
    ..In addition, the extent of uncoupling of NADPH oxidation from product formation, a process leading to futile production of H(2)O(2), increased significantly during the metabolism of ethylbenzene as a result of the inactivation...
  33. ncbi The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9
    Ute M Kent
    Department of Pharmacology, The University of Michigan, MI 48109 0632, USA
    Drug Metab Dispos 30:709-15. 2002
    ..Heme and reduced CO spectral analysis also indicated that glabridin inactivated P450s 2B6 and 3A4 by different mechanisms...
  34. ncbi The highly conserved Glu149 and Tyr190 residues contribute to peroxynitrite-mediated nitrotyrosine formation and the catalytic activity of cytochrome P450 2B1
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 4810, USA
    Chem Res Toxicol 18:1203-10. 2005
    ..Since Glu149 and Tyr190 are both highly conserved in the P450 2 family, they may play an important role in the tertiary structure and functional properties of these P450s...
  35. pmc Mechanism-based inactivation of CYP2B1 and its F-helix mutant by two tert-butyl acetylenic compounds: covalent modification of prosthetic heme versus apoprotein
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    J Pharmacol Exp Ther 331:392-403. 2009
    ..Homology modeling and substrate docking studies were presented to facilitate the interpretation of the experimental results...
  36. pmc Differential inhibition of cytochromes P450 3A4 and 3A5 by the newly synthesized coumarin derivatives 7-coumarin propargyl ether and 7-(4-trifluoromethyl)coumarin propargyl ether
    Chitra Sridar
    Department of Pharmacology, The University of Michigan, 1150 West Medical Center Dr, Ann Arbor, MI 48109 5632, USA
    Drug Metab Dispos 36:2234-43. 2008
    ..Metabolism studies using TFCPE resulted in the identification of a single metabolite that is formed by P450 3A4 but not by P450 3A5 and that may play a role in the mechanism-based inactivation...
  37. pmc Covalent modification of Thr302 in cytochrome P450 2B1 by the mechanism-based inactivator 4-tert-butylphenylacetylene
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    J Pharmacol Exp Ther 333:663-9. 2010
    ....
  38. ncbi The inactivation of cytochrome P450 3A5 by 17alpha-ethynylestradiol is cytochrome b5-dependent: metabolic activation of the ethynyl moiety leads to the formation of glutathione conjugates, a heme adduct, and covalent binding to the apoprotein
    Hsia lien Lin
    Department of Pharmacology, 2301 MSRB III, 1150 West Medical Center Dr, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 321:276-87. 2007
    ....
  39. pmc Gender dimorphic formation of mouse Mallory-Denk bodies and the role of xenobiotic metabolism and oxidative stress
    Shinichiro Hanada
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 5622, USA
    Gastroenterology 138:1607-17. 2010
    ..Given the significant gender differences in predisposition to human alcohol-related liver injury, and the strain difference in mouse MDB formation, we hypothesized that sex affects MDB formation...
  40. pmc tert-Butylphenylacetylene is a potent mechanism-based inactivator of cytochrome P450 2B4: inhibition of cytochrome P450 catalysis by steric hindrance
    Haoming Zhang
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109 5632, USA
    Mol Pharmacol 76:1011-8. 2009
    ..This large discrepancy in the stimulation of the first electron transfer by benzphetamine strongly suggests that the impairment of P450 catalysis is due to inhibition of benzphetamine binding to the tBPA-modified P450 2B4...
  41. ncbi Identification of amino acid residues involved in the inactivation of cytochrome P450 2B1 by two acetylenic compounds: the role of three residues in nonsubstrate recognition Sites
    Linda B von Weymarn
    Department of Pharmacology, The University of Michigan, 1150 West Medical Center Dr, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 311:71-9. 2004
    ..These results demonstrate that substitution of three non-SRS residues in P450 2B1 leads to protection against inactivation of 2B enzymes by these two acetylenic compounds...
  42. ncbi The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine
    Monica I Jushchyshyn
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 31:46-52. 2003
    ..5:1 (PCP/p450). In the presence of GSH, the stoichiometry was 1:1. This stoichiometry was further supported using electrospray ionization-liquid chromatography-mass spectrometry to analyze PCP-inactivated p450 2B1, 2B4, and 2B6...
  43. ncbi Metabolism of bergamottin by cytochromes P450 2B6 and 3A5
    Ute M Kent
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 318:992-1005. 2006
    ....
  44. ncbi Roles of the threonine 407, aspartic acid 417, and threonine 419 residues in P450 2B1 in metabolism
    Chitra Sridar
    Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
    Biochem Biophys Res Commun 338:386-93. 2005
    ..Metabolism of 17EE by 2B1 supported by these alternate oxidants revealed differences in the metabolites that may be related to the inability of 2B1 to be inactivated under these conditions...
  45. pmc Oxygen activation by cytochrome P450 monooxygenase
    Djemel Hamdane
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109, USA
    Photosynth Res 98:657-66. 2008
    ..In this article, we review recent advances in understanding the molecular mechanisms by which P450 activates dioxygen...
  46. ncbi Effects of 8-methoxypsoralen on cytochrome P450 2A13
    Linda B von Weymarn
    Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
    Carcinogenesis 26:621-9. 2005
    ..This mass shift correlates with the addition of one molecule of 8-MOP plus one atom of oxygen atom to the P450 apoprotein...
  47. ncbi Formation of a novel reversible cytochrome P450 spectral intermediate: role of threonine 303 in P450 2E1 inactivation
    Anna L Blobaum
    Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109 0632, USA
    Biochemistry 43:11942-52. 2004
    ..Together, these data support a role for the highly conserved T303 residue in proton delivery to the active site of P450 2E1 and in the inactivation of the 2E1 P450s by small acetylenic compounds...
  48. ncbi The functional role of threonine-205 in the mechanism-based inactivation of P450 2B1 by two ethynyl substrates: the importance of the F helix in catalysis
    Hsia lien Lin
    Department of Pharmacology, 2301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 311:855-63. 2004
    ..The site-specific mutation of one residue, Thr-205 to Val, is sufficient to alter the profile of products formed during 17EE metabolism, such that very low levels of metabolite C are formed and inactivation is essentially abolished...
  49. ncbi Mutation of tyrosine 190 to alanine eliminates the inactivation of cytochrome P450 2B1 by peroxynitrite
    Hsia lien Lin
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Chem Res Toxicol 16:129-36. 2003
    ..Modeling studies suggest that Tyr 190 may play a structural role in maintaining the integrity of the protein for maximal activity through hydrogen bonding with Glu 149...
  50. ncbi Novel reversible inactivation of cytochrome P450 2E1 T303A by tert-butyl acetylene: the role of threonine 303 in proton delivery to the active site of cytochrome P450 2E1
    Anna L Blobaum
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 0632, USA
    J Pharmacol Exp Ther 310:281-90. 2004
    ....
  51. ncbi Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes
    Paul F Hollenberg
    The University of Michigan, Ann Arbor, USA
    Drug Metab Rev 34:17-35. 2002
  52. pmc Cross-linking of human cytochrome P450 2B6 to NADPH-cytochrome P450 reductase: Identification of a potential site of interaction
    Namandjé N Bumpus
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 5632, United States
    J Inorg Biochem 104:485-8. 2010
    ..Taken together, these studies indicate that residues in the C-helix of P450 2B6 play a major role in the interaction with the P450 reductase...
  53. ncbi P450 active site architecture and reversibility: inactivation of cytochromes P450 2B4 and 2B4 T302A by tert-butyl acetylenes
    Anna L Blobaum
    Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109, USA
    Biochemistry 44:3831-44. 2005
    ....
  54. ncbi The naturally occurring cytochrome P450 (P450) 2B6 K262R mutant of P450 2B6 exhibits alterations in substrate metabolism and inactivation
    Namandjé N Bumpus
    Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0632, USA
    Drug Metab Dispos 33:795-802. 2005
    ..The KI values for inactivation of the variant were significantly greater than those determined for the wild-type enzyme. These data demonstrate a functional difference between P450 Delta2B6 and the allelic variant P450 Delta2B6 K262R...
  55. pmc Effect of conformational dynamics on substrate recognition and specificity as probed by the introduction of a de novo disulfide bond into cytochrome P450 2B1
    Haoming Zhang
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 284:25678-86. 2009
    ..Taken together, these results suggest that protein dynamics play an important role in regulating substrate entry and recognition...
  56. pmc A cytochrome P450-derived epoxygenated metabolite of anandamide is a potent cannabinoid receptor 2-selective agonist
    Natasha T Snider
    Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    Mol Pharmacol 75:965-72. 2009
    ..Combined, our results suggest that epoxidation of anandamide by P450s to form 5,6-EET-EA represents an endocannabinoid bioactivation pathway in the context of immune cell function...
  57. pmc The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6
    Natasha T Snider
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 5632, USA
    J Pharmacol Exp Ther 327:538-45. 2008
    ..This study also offers support to the hypothesis that neuropsychiatric phenotype differences among individuals with genetic variations in CYP2D6 could be ascribable to interactions of this enzyme with endogenous substrates...
  58. ncbi Metabolism of efavirenz and 8-hydroxyefavirenz by P450 2B6 leads to inactivation by two distinct mechanisms
    Namandjé N Bumpus
    Department of Pharmacology, The University of Michigan, 1150 W Medical Center Dr, Ann Arbor, MI 48109 0632, USA
    J Pharmacol Exp Ther 318:345-51. 2006
    ....
  59. pmc Mechanism-based inactivation of human cytochrome P450 2B6 by clopidogrel: involvement of both covalent modification of cysteinyl residue 475 and loss of heme
    Haoming Zhang
    Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109 5632, USA
    Mol Pharmacol 80:839-47. 2011
    ..Collectively, these results suggest that clopidogrel inactivates CYP2B6 primarily through destruction of the heme, whereas 2-oxo-clopidogrel inactivates CYP2B6 through covalent modification of Cys475...
  60. pmc Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4-CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450-reductase complex
    Haoming Zhang
    Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 5632, USA
    J Pharmacol Exp Ther 338:803-9. 2011
    ..8 from forming a functional complex with CPR. Results from this work provide further insights to better understand the genotype-phenotype correlation regarding CYP2B6 polymorphisms and drug metabolism...
  61. pmc Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6
    Chitra Sridar
    Department of Pharmacology, University of Michigan, 1150 W Medical Center Dr, Ann Arbor, MI 48109 5632, USA
    Drug Metab Dispos 39:782-8. 2011
    ....
  62. ncbi Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13: potential for chemoprevention in smokers
    Linda B von Weymarn
    Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
    Carcinogenesis 27:782-90. 2006
    ....
  63. ncbi Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma
    Hassan R Dhaini
    Department of Environmental Health Sciences, Toxicology Program, University of Michigan, Ann Arbor 48109, USA
    J Clin Oncol 21:2481-5. 2003
    ..One of these, CYP3A4/5 is involved in metabolic activation and detoxification of a wide number of carcinogens and chemotherapeutic agents, including many drugs that are useful in the treatment of osteosarcomas...
  64. ncbi Alteration of the heme prosthetic group of neuronal nitric-oxide synthase during inactivation by N(G)-amino-L-arginine in vitro and in vivo
    Jennifer L Vuletich
    Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109 0632, USA
    Mol Pharmacol 62:110-8. 2002
    ..Because inactivation and alteration may trigger ubiquitination and proteasomal degradation of nNOS, NAA may be a useful biochemical tool for the study of these basic regulatory processes...
  65. pmc Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines
    Edith J Mensah-Osman
    Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
    Cancer 109:957-65. 2007
    ....
  66. ncbi The mechanism-based inactivation of p450 2B4 by tert-butyl 1-methyl-2-propynyl ether: structural determination of the adducts to the p450 heme
    Linda B von Weymarn
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Arch Biochem Biophys 425:95-105. 2004
    ..The spectra were consistent with a tBMP molecule and an oxygen atom attached to iron-depleted heme. Proton NMR studies suggest that the two modified hemes in p450 2B1 are N-alkylated on pyrrole rings A and D...

Research Grants19

  1. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2009
    ....
  2. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2007
    ....
  3. INTERDEPARTMENTAL TRAINING IN PHARMACOLOGICAL SCIENCES
    Paul Hollenberg; Fiscal Year: 2007
    ..Rigorous policies of admissions, course grades, qualifying exams, laboratory experiences, and thesis work are enforced to maintain a high level of quality. ..
  4. Hemeprotein--Catalyzed Oxygenerations of Carcinogens
    Paul Hollenberg; Fiscal Year: 2005
    ..Results of the these studies could provide information that will be extremely valuable in developing methods to decrease the risk of developing cancer. ..
  5. HEMEPROTEIN--CATALYZED OXYGENATIONS OF CARCINOGENS
    Paul Hollenberg; Fiscal Year: 2000
    ..The results of these studies could provide information for developing methods to decrease the risk of developing cancer. ..
  6. Hemeprotein-catalyzed Oxygenations of Carcinogens
    Paul F Hollenberg; Fiscal Year: 2010
    ....