pregnenolone carbonitrile

Summary

Summary: A catatoxic steroid and microsomal enzyme inducer having significant effects on the induction of cytochrome P450. It has also demonstrated the potential for protective capability against acetaminophen-induced liver damage.

Top Publications

  1. Guzelian J, Barwick J, Hunter L, Phang T, Quattrochi L, Guzelian P. Identification of genes controlled by the pregnane X receptor by microarray analysis of mRNAs from pregnenolone 16alpha-carbonitrile-treated rats. Toxicol Sci. 2006;94:379-87 pubmed
    ..Our results support the idea that the domain of PXR-controlled gene networks may be even more extensive than currently thought and may extend to functions apart from xenobiotic metabolism. ..
  2. Staudinger J, Liu Y, Madan A, Habeebu S, Klaassen C. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab Dispos. 2001;29:1467-72 pubmed
    ..Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo. ..
  3. Staudinger J, Goodwin B, Jones S, Hawkins Brown D, MacKenzie K, LaTour A, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. 2001;98:3369-74 pubmed
    ..These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease. ..
  4. He J, Nishida S, Xu M, Makishima M, Xie W. PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts. Gastroenterology. 2011;140:2095-106 pubmed publisher
    ..PXR prevented CGD via its coordinate regulation of the biosynthesis and transport of bile salts in the liver and intestine. PXR maintains biliary bile acid homeostasis and may be developed as a therapeutic target for CGD. ..
  5. Sartori E, Delaforge M. Specific drug binding to rat liver cytochrome P-450 isozymes induced by pregnenolone-16 alpha-carbonitrile and macrolide antibiotics. Implications for drug interactions. Chem Biol Interact. 1990;73:297-307 pubmed
  6. Vansell N, Muppidi J, Habeebu S, Klaassen C. Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB). Toxicol Sci. 2004;81:50-9 pubmed
    ..However, thyroid carcinomas stemming from PCB treatment indicate that separate mechanisms exist for the production of thyroid cancer in rodents by chemicals classically considered microsomal enzyme inducers. ..
  7. Casey S, Blumberg B. The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver. Mol Endocrinol. 2012;26:916-25 pubmed publisher
    ..These data support our previous findings that SXR functions as a tumor suppressor in B-1 lymphocytes and establish a unique role for SXR as a modulator of developmental hematopoiesis in the liver. ..
  8. Jimenez B, Maldonado L, Dahl R, Quattrochi L, Guzelian P. Ectopic expression of MHC class II genes (RT1.B(I) beta/alpha) in rat hepatocytes in vivo and in culture can be elicited by treatment with the pregnane X receptor agonists pregnenolone 16 alpha-carbonitrile and dexamethasone. Life Sci. 2002;71:311-23 pubmed
    ..The concept of a set of genes coordinately controlled to maintain homeostasis in parenchymal tissues during toxic stress must now be extended to include the immune system. ..
  9. Zhang B, Cheng Q, Ou Z, Lee J, Xu M, Kochhar U, et al. Pregnane X receptor as a therapeutic target to inhibit androgen activity. Endocrinology. 2010;151:5721-9 pubmed publisher
    ..In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer. ..

More Information

Publications62

  1. Burger H, Schuetz J, Schuetz E, Guzelian P. Paradoxical transcriptional activation of rat liver cytochrome P-450 3A1 by dexamethasone and the antiglucocorticoid pregnenolone 16 alpha-carbonitrile: analysis by transient transfection into primary monolayer cultures of adult rat hepatocytes. Proc Natl Acad Sci U S A. 1992;89:2145-9 pubmed
    ..We conclude that a primary mechanism for induction of CYP3A1 is stimulated transcription through a pathway activated by steroid hormones. ..
  2. Squires E, Sueyoshi T, Negishi M. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem. 2004;279:49307-14 pubmed
    ..We conclude that the CCRP mediates the retention of PXR in the cytosol and modulates the activation of PXR in response to PCN treatment. ..
  3. Matheny C, Ali R, Yang X, Pollack G. Effect of prototypical inducing agents on P-glycoprotein and CYP3A expression in mouse tissues. Drug Metab Dispos. 2004;32:1008-14 pubmed
    ..Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations. ..
  4. Nakamura K, Moore R, Negishi M, Sueyoshi T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem. 2007;282:9768-76 pubmed
    ..These results are consistent with the conclusion that PCN-activated PXR represses FoxA2-mediated transcription of Ctp1a and Hmgcs2 genes in fasting liver. ..
  5. Honda A, Miyazaki T, Ikegami T, Iwamoto J, Maeda T, Hirayama T, et al. Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res. 2011;52:1509-16 pubmed publisher
    ..650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol. ..
  6. Hukkanen J, Rysa J, Mäkelä K, Herzig K, Hakkola J, Savolainen M. The effect of pregnane X receptor agonists on postprandial incretin hormone secretion in rats and humans. J Physiol Pharmacol. 2015;66:831-9 pubmed
    ..The regulation of glucagon secretion by PXR may be sexually dimorphic in humans. The mechanism of disrupted glucose metabolism induced by PXR activation requires further study. ..
  7. Miyata M, Nomoto M, Sotodate F, Mizuki T, Hori W, Nagayasu M, et al. Possible protective role of pregnenolone-16 alpha-carbonitrile in lithocholic acid-induced hepatotoxicity through enhanced hepatic lipogenesis. Eur J Pharmacol. 2010;636:145-54 pubmed publisher
    ..These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity. ..
  8. Lake B, Renwick A, Cunninghame M, Price R, Surry D, Evans D. Comparison of the effects of some CYP3A and other enzyme inducers on replicative DNA synthesis and cytochrome P450 isoforms in rat liver. Toxicology. 1998;131:9-20 pubmed
    ..These studies demonstrate that while CYP2B and CYP4A enzyme inducers may stimulate replicative DNA synthesis, only some CYP3A enzyme inducers are mitogenic agents in rat liver. ..
  9. Beilke L, Aleksunes L, Olson E, Besselsen D, Klaassen C, Dvorak K, et al. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice. Toxicol Lett. 2009;188:38-44 pubmed publisher
    ..This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression. ..
  10. Lau A, Yang G, Rajaraman G, Baucom C, Chang T. Human pregnane X receptor agonism by Ginkgo biloba extract: assessment of the role of individual ginkgolides. J Pharmacol Exp Ther. 2010;335:771-80 pubmed publisher
    ..Our findings provide insights into the biological and chemical mechanisms of hPXR activation by G. biloba extract. ..
  11. Moriya N, Kataoka H, Nishikawa J, Kugawa F. Identification of Candidate Target Cyp Genes for microRNAs Whose Expression Is Altered by PCN and TCPOBOP, Representative Ligands of PXR and CAR. Biol Pharm Bull. 2016;39:1381-6 pubmed publisher
    ..Further studies will be required to fully elucidate the miRNA regulatory mechanisms that contribute to modulating CYP expression. ..
  12. Meredith C, Scott M, Renwick A, Price R, Lake B. Studies on the induction of rat hepatic CYP1A, CYP2B, CYP3A and CYP4A subfamily form mRNAs in vivo and in vitro using precision-cut rat liver slices. Xenobiotica. 2003;33:511-27 pubmed
    ..9. The results demonstrate the utility of cultured precision-cut liver slices as an in vitro model system to evaluate the effects of xenobiotics on rat CYP1A, CYP2B, CYP3A and CYP4A form mRNA levels...
  13. Handschin C, Podvinec M, Stöckli J, Hoffmann K, Meyer U. Conservation of signaling pathways of xenobiotic-sensing orphan nuclear receptors, chicken xenobiotic receptor, constitutive androstane receptor, and pregnane X receptor, from birds to humans. Mol Endocrinol. 2001;15:1571-85 pubmed
    ..These results indicate that closely related nuclear receptors, transcription factors, and signaling pathways are mediating the transcriptional activation of multiple genes by xenobiotics in chicken, rodents, and man. ..
  14. Igarashi K, Kitajima S, Aisaki K, Tanemura K, Taquahashi Y, Moriyama N, et al. Development of humanized steroid and xenobiotic receptor mouse by homologous knock-in of the human steroid and xenobiotic receptor ligand binding domain sequence. J Toxicol Sci. 2012;37:373-80 pubmed
  15. Marek C, Tucker S, Konstantinou D, Elrick L, Haefner D, Sigalas C, et al. Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms. Biochem J. 2005;387:601-8 pubmed
    ..These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis. ..
  16. Zhang W, Purchio A, Chen K, Wu J, Lu L, Coffee R, et al. A transgenic mouse model with a luciferase reporter for studying in vivo transcriptional regulation of the human CYP3A4 gene. Drug Metab Dispos. 2003;31:1054-64 pubmed
    ..Our results suggest that the human CYP3A4 promoter functions in transgenic mice and that this in vivo model can be used to study transcriptional regulation of the CYP3A4 gene. ..
  17. Ladona M, Spalding D, Ekman L, Linström B, Rane A. Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids. Biochem Pharmacol. 1989;38:3147-55 pubmed
    ..These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver. ..
  18. Kourounakis P, Rekka E, Demopoulos V, Retsas S. Effect of the position of the cyano-group of cyanopregnenolones on their drug metabolic inducing activity. Eur J Drug Metab Pharmacokinet. 1991;16:9-13 pubmed
    ..The poor performance of pregnenolone-16 alpha-acetonitrile was attributed to electronic effects. A hypothesis of some structural features of the receptor site for its interaction with the cyanopregnenolone inducers was presented. ..
  19. Ma Y, Sachdeva K, Liu J, Song X, Li Y, Yang D, et al. Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23. Biochem Pharmacol. 2005;69:1363-71 pubmed
    ..The interaction between PXR inducer and ligand provides a novel mechanism on how functionally and structurally distinct chemicals cooperatively regulate the expression of xenobiotic-metabolizing enzymes and transporters. ..
  20. Fernald G, Altman R. Using molecular features of xenobiotics to predict hepatic gene expression response. J Chem Inf Model. 2013;53:2765-73 pubmed publisher
    ..Finally, a detailed analysis of the CYP1A2 predictor allowed us to identify which fragments made significant contributions to the predictive scores. ..
  21. Maeda T, Oyabu M, Yotsumoto T, Higashi R, Nagata K, Yamazoe Y, et al. Effect of pregnane X receptor ligand on pharmacokinetics of substrates of organic cation transporter Oct1 in rats. Drug Metab Dispos. 2007;35:1580-6 pubmed
    ..Because PXR ligands include various clinically used drugs, alterations of hepatic drug handling may arise from interactions between cationic drugs that are substrates of Oct1 and ligands of PXR. ..
  22. de Haan W, de Vries van der Weij J, Mol I, Hoekstra M, Romijn J, Jukema J, et al. PXR agonism decreases plasma HDL levels in ApoE3-Leiden.CETP mice. Biochim Biophys Acta. 2009;1791:191-7 pubmed publisher
    ..We conclude that chronic PXR agonism dose-dependently reduces plasma HDL-cholesterol in the presence of CETP...
  23. Song X, Li Y, Liu J, Mukundan M, Yan B. Simultaneous substitution of phenylalanine-305 and aspartate-318 of rat pregnane X receptor with the corresponding human residues abolishes the ability to transactivate the CYP3A23 promoter. J Pharmacol Exp Ther. 2005;312:571-82 pubmed
    ..The decreased responsiveness toward PCN and reduced basal transcriptional activity suggest that Phe-305 and Asp-318 are involved in both ligand-binding and corepressor interactions. ..
  24. Lampe M, Kammerer R. Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro. Carcinogenesis. 1987;8:1525-9 pubmed
    ..These data suggest that MPH is metabolically activated to a species which binds to DNA and that this activation may be mediated by cytochrome P-450 isozymes...
  25. Gonzalez F, Nebert D, Hardwick J, Kasper C. Complete cDNA and protein sequence of a pregnenolone 16 alpha-carbonitrile-induced cytochrome P-450. A representative of a new gene family. J Biol Chem. 1985;260:7435-41 pubmed
  26. Schuetz E, Schmid W, Schutz G, Brimer C, Yasuda K, Kamataki T, et al. The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver. Drug Metab Dispos. 2000;28:268-78 pubmed
    ..Thus, there are distinctly different essential requirements of CYP3A, CYP2B, and P-450 reductase genes for the glucocorticoid receptor in their induction by steroids and drugs. ..
  27. Farrar N, Prevedouros K, Harner T, Sweetman A, Jones K. Continental scale passive air sampling of persistent organic pollutants using rapidly equilibrating thin films (POGs). Environ Pollut. 2006;144:423-33 pubmed
    ..Spatial variation was strongly influenced by air mass origin, with lower levels being observed at most sites impacted by maritime air masses. ..
  28. Amacher D, Schomaker S, Retsema J. Comparison of the effects of the new azalide antibiotic, azithromycin, and erythromycin estolate on rat liver cytochrome P-450. Antimicrob Agents Chemother. 1991;35:1186-90 pubmed
    ..In contrast to erythromycin estolate, azithromycin is not expected to inhibit its own metabolism or that of other drugs via this pathway. ..
  29. Gahir S, Piquette Miller M. Gestational and pregnane X receptor-mediated regulation of placental ATP-binding cassette drug transporters in mice. Drug Metab Dispos. 2011;39:465-71 pubmed publisher
    ..Overall, our results suggest a repressive role of PXR in the basal expression of several placental transporters and a tissue-specific induction of these target genes after PXR activation...
  30. Ma X, Cheung C, Krausz K, Shah Y, Wang T, Idle J, et al. A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4. Drug Metab Dispos. 2008;36:2506-12 pubmed publisher
    ..These results suggest that the TgCYP3A4/hPXR mouse model could serve as a useful tool for studies on CYP3A4 transcription and function in vivo. ..
  31. Xu C, Wang X, Staudinger J. Regulation of tissue-specific carboxylesterase expression by pregnane x receptor and constitutive androstane receptor. Drug Metab Dispos. 2009;37:1539-47 pubmed publisher
    ..Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans. ..
  32. Franklin M, Phillips J, Kushner J. CYP3A-inducing agents and the attenuation of uroporphyrin accumulation and excretion in a rat model of porphyria cutanea tarda. Biochem Pharmacol. 2000;60:1325-31 pubmed
  33. LeCluyse E. Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact. 2001;134:283-9 pubmed
    ..Furthermore, sequence differences in the ligand-binding domain, and not the DNA binding domain, appear to serve as the molecular basis for the species differences in CYP3A induction observed in vivo. ..
  34. Tanino T, Nawa A, Nakao M, Noda M, Fujiwara S, Iwaki M. Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2'-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes. J Pharm Pharmacol. 2009;61:1029-35 pubmed publisher
    ..The findings have provided an important step towards identifying a key transporter in hepatic detoxification of paclitaxel and TAX-2'-Et in small animals. ..
  35. Li D, Moorthy B, Chen S, Randerath K. Effects of cytochrome P450 inducers on I-compounds in rat liver and kidney DNA. Carcinogenesis. 1992;13:1191-8 pubmed
    ..These results suggest a major role for cytochrome P450 enzymes in the metabolism of I-compounds. ..
  36. Yu A, Fukamachi K, Krausz K, Cheung C, Gonzalez F. Potential role for human cytochrome P450 3A4 in estradiol homeostasis. Endocrinology. 2005;146:2911-9 pubmed
    ..This may be of concern for treatment of pregnant and lactating women because CYP3A4 gene expression and enzymatic activity can be potentially modified by CYP3A4 inhibitors or inducers in medications, supplements, beverages, and diet. ..
  37. Ohmori S, Horie T, Guengerich F, Kiuchi M, Kitada M. Purification and characterization of two forms of hepatic microsomal cytochrome P450 from untreated cynomolgus monkeys. Arch Biochem Biophys. 1993;305:405-13 pubmed
    ..These results demonstrate that this P450 enzyme is in the P450 3A subfamily. ..
  38. Konno Y, Kamino H, Moore R, Lih F, Tomer K, Zeldin D, et al. The nuclear receptors constitutive active/androstane receptor and pregnane x receptor activate the Cyp2c55 gene in mouse liver. Drug Metab Dispos. 2010;38:1177-82 pubmed publisher
    ..Chronic PB treatment increased hepatic microsomal CYP2C55 protein and serum 19-HETE levels. These findings indicate that CAR and PXR may play a role in regulation of drug-induced synthesis of 19-HETE in the mouse. ..
  39. Vansell N, Klaassen C. Effect of microsomal enzyme inducers on the biliary excretion of triiodothyronine (T(3)) and its metabolites. Toxicol Sci. 2002;65:184-91 pubmed
    ..These findings indicate that PCN increases the glucuronidation and biliary excretion of T(3) in vivo, and suggest that enhanced elimination of T(3) may be the mechanism responsible for the increases in serum TSH caused by PCN. ..
  40. Cho J, Kang D, Ma X, Ahn S, Krausz K, LUECKE H, et al. Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation. J Lipid Res. 2009;50:924-37 pubmed publisher
    ..Activation of PXR results in attenuated levels of the two vitamin E conjugates that may be useful as biomarkers of PXR activation. ..
  41. Lupp A, Glöckner R, Etzrodt J, Muller D. Precision-cut liver slices from rats of different ages: basal cytochrome P450-dependent monooxygenase activities and inducibility. Anal Bioanal Chem. 2008;392:1173-84 pubmed publisher
    ..Thus, precision-cut rat liver slices are a suitable in vitro tool for investigating age-related changes in CYP activities and induction as well as developmental differences in drug metabolism and toxicity. ..
  42. Ejiri N, Katayama K, Doi K. Induction of CYP3A1 by dexamethasone and pregnenolone-16alpha-carbonitrile in pregnant rat and fetal livers and placenta. Exp Toxicol Pathol. 2003;54:273-9 pubmed
    ..These results suggest that DEX and PCN might pass through the placenta with no prominent induction of CYP3A1 at the placenta and be distributed to the fetal liver rapidly, resulting in high induction of CYP3A1 in the fetal liver. ..
  43. Nelson D, Bhaskaran V, Foster W, Lehman McKeeman L. p53-independent induction of rat hepatic Mdm2 following administration of phenobarbital and pregnenolone 16alpha-carbonitrile. Toxicol Sci. 2006;94:272-80 pubmed
  44. Smith E, Wilson J. Assessment of cytochrome P450 fluorometric substrates with rainbow trout and killifish exposed to dexamethasone, pregnenolone-16alpha-carbonitrile, rifampicin, and beta-naphthoflavone. Aquat Toxicol. 2010;97:324-33 pubmed publisher
    ..Overall, many of these catalytic assays could be valuable tools for identification of the function of specific CYP subfamilies and individual isoforms in fish. ..
  45. Shaw H, Chen W. Effects of pregnenolone-16alpha-carbonitrile on vitamin E status and protein levels of antioxidant enzymes in male rats fed a vitamin E-supplemented diet. Redox Rep. 2009;14:61-8 pubmed publisher
  46. Zhu B, Kosh J, Fu J, Cai M, Xu S, Conney A. Strong inhibition of estrone-3-sulfatase activity by pregnenolone 16alpha-carbonitrile but not by several analogs lacking a 16alpha-nitrile group. Steroids. 2000;65:521-7 pubmed
    ..This knowledge may be useful for the rational design of more potent steroidal inhibitors of E(1)-3-sulfatase by introducing an additional nitrile group to their C16alpha-position. ..
  47. Surry D, McAllister G, Meneses Lorente G, Evans D. High throughput ribonuclease protection assay for the determination of CYP3A mRNA induction in cultured rat hepatocytes. Xenobiotica. 1999;29:827-38 pubmed
    ..The system has the potential to screen for overall CYP3A mRNA induction in response to compounds at an early stage in drug research...
  48. Amacher D, Schomaker S. Ethylmorphine N-demethylase activity as a marker for cytochrome P450 CYP3A activity in rat hepatic microsomes. Toxicol Lett. 1998;94:115-25 pubmed
  49. Felmlee M, Lon H, Gonzalez F, Yu A. Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice. Drug Metab Dispos. 2008;36:435-41 pubmed
    ..The difference in CYP3A4 expression and induction between male and female mice suggests that women may be more susceptible to CYP3A4-mediated drug-drug interactions, and the extent of drug-drug interactions could be substrate dependent. ..
  50. Kocarek T, Shenoy S, Mercer Haines N, Runge Morris M. Use of dominant negative nuclear receptors to study xenobiotic-inducible gene expression in primary cultured hepatocytes. J Pharmacol Toxicol Methods. 2002;47:177-87 pubmed
  51. Ma Y, Liu D. Activation of pregnane X receptor by pregnenolone 16 ?-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. PLoS ONE. 2012;7:e38734 pubmed publisher
    ..These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance. ..
  52. Ejiri N, Katayama K, Kiyosawa N, Baba Y, Doi K. Microarray analysis on Phase II drug metabolizing enzymes expression in pregnant rats after treatment with pregnenolone-16alpha-carbonitrile or phenobarbital. Exp Mol Pathol. 2005;79:272-7 pubmed
    ..This is the first report of the gene expression profiles of Phase II drug metabolizing enzymes in pregnant rat and fetal livers and placenta after treatment with typical inducers of drug metabolizing enzymes. ..
  53. Argikar U, Senekeo Effenberger K, Larson E, Tukey R, Remmel R. Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009;39:826-35 pubmed publisher
    ..This study demonstrates the successful application of Tg-UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of UGT1A4 substrates. ..