Genomes and Genes
Gene Symbol: actb1
Description: actin, beta 1
Alias: ACTB, B-ACTZF, actba, bact, bactin1, bactzf, wu:fd18f05, actin, cytoplasmic 1, beta-actin, beta-actin-1
- Muncke J, Eggen R. Vitellogenin 1 mRNA as an early molecular biomarker for endocrine disruption in developing zebrafish (Danio rerio). Environ Toxicol Chem. 2006;25:2734-41 pubmed..These findings show that vtg1 is regularly expressed in developing zebrafish and that it is inducible by EE2. We propose the use of vtg1 as molecular target for estrogenicity in the MolDarT. ..
- Liu Y, Wang J, Fang X, Zhang H, Dai J. The thyroid-disrupting effects of long-term perfluorononanoate exposure on zebrafish (Danio rerio). Ecotoxicology. 2011;20:47-55 pubmed publisher..Our results provide the first evidence for the thyroid-disrupting effects of long-term PFNA exposure in zebrafish. ..
- Wei S, Zhou J, Chen X, Shah R, Liu J, Orcutt T, et al. The zebrafish activating immune receptor Nitr9 signals via Dap12. Immunogenetics. 2007;59:813-21 pubmed
- Chen H, Contreras X, Yamaguchi Y, Handa H, Peterlin B, Guo S. Repression of RNA polymerase II elongation in vivo is critically dependent on the C-terminus of Spt5. PLoS ONE. 2009;4:e6918 pubmed publisher..Together, these results reveal a dominant activity of NSpt5 to de-repress RNAPII elongation, and suggest that the C-terminus of Spt5 is critical for repressing RNAPII elongation in vivo. ..
- Zeng Z, Richardson J, Verduzco D, Mitchell D, Patton E. Zebrafish have a competent p53-dependent nucleotide excision repair pathway to resolve ultraviolet B-induced DNA damage in the skin. Zebrafish. 2009;6:405-15 pubmed publisher..These studies provide the groundwork for exploring the role of UV light in melanoma development in zebrafish. ..
- Chablais F, Jazwinska A. IGF signaling between blastema and wound epidermis is required for fin regeneration. Development. 2010;137:871-9 pubmed publisher..Thus, IGF signaling upregulated upon fin amputation represents a signal from the blastema to the wound epithelium, a crucial step in appendage regeneration. ..
- Hermann A, Kim C. Effects of arsenic on zebrafish innate immune system. Mar Biotechnol (NY). 2005;7:494-505 pubmed..Differences in IFN and MX : expression in arsenic-exposed larvae point toward an interruption of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway. ..
- García López A, De Jonge H, Nóbrega R, de Waal P, van Dijk W, Hemrika W, et al. Studies in zebrafish reveal unusual cellular expression patterns of gonadotropin receptor messenger ribonucleic acids in the testis and unexpected functional differentiation of the gonadotropins. Endocrinology. 2010;151:2349-60 pubmed publisher
- Miyamura N, Hirayama J, Sawanobori K, Tamaru T, Asaoka Y, Honda R, et al. CLOCK:BMAL-independent circadian oscillation of zebrafish Cryptochrome1a gene. Biol Pharm Bull. 2009;32:1183-7 pubmed
- Cambier S, Benard G, Mesmer Dudons N, Gonzalez P, Rossignol R, Brethes D, et al. At environmental doses, dietary methylmercury inhibits mitochondrial energy metabolism in skeletal muscles of the zebra fish (Danio rerio). Int J Biochem Cell Biol. 2009;41:791-9 pubmed publisher..This was confirmed by the analysis of gene expression levels, using RT-PCR. Our study provides a basis for further analysis of the deleterious effect of MeHg on fish health via mitochondrial impairment. ..
- Wang X, Zhou S, Ding X, Zhu G, Guo J. Effect of triazophos, fipronil and their mixture on miRNA expression in adult zebrafish. J Environ Sci Health B. 2010;45:648-57 pubmed publisher..MiRNAs might present a novel toxicological response that could be used as a toxicological biomarker and have a different direction for future investigations of their association with miRNAs involved in chemical related diseases. ..
- Watzke J, Schirmer K, Scholz S. Bacterial lipopolysaccharides induce genes involved in the innate immune response in embryos of the zebrafish (Danio rerio). Fish Shellfish Immunol. 2007;23:901-5 pubmed..The gene induction required the removal of the chorion prior to lipopolysaccharide exposure. ..
- Hoffmann J, Oris J. Altered gene expression: a mechanism for reproductive toxicity in zebrafish exposed to benzo[a]pyrene. Aquat Toxicol. 2006;78:332-40 pubmed
- Wang L, Chen D, Yang L, Huang S, Zhang Y, Zhang H. Expression patterns of the creatine metabolism-related molecules AGAT, GAMT and CT1 in adult zebrafish Danio rerio. J Fish Biol. 2010;76:1212-9 pubmed publisher..rerio were investigated. The results reveal that AGAT, GAMT and CT1 are expressed widely in diverse tissues of D. rerio where the homologous genes in mammals are also expressed. ..
- Moss L, Monette M, Jaso Friedmann L, Leary J, Dougan S, Krunkosky T, et al. Identification of phagocytic cells, NK-like cytotoxic cell activity and the production of cellular exudates in the coelomic cavity of adult zebrafish. Dev Comp Immunol. 2009;33:1077-87 pubmed publisher..E. coli injected into the CC were phagocytosed in a dose and time dependent fashion by granulocytes, monocytes and macrophages. NCC lysed mammalian target cells and NCAMP-1 expressing hybridoma cells in redirected lysis assays. ..
- Nicoli S, Tobia C, Gualandi L, De Sena G, Presta M. Calcitonin receptor-like receptor guides arterial differentiation in zebrafish. Blood. 2008;111:4965-72 pubmed publisher..These data demonstrate that crlr plays a nonredundant role in arterial differentiation, representing a novel element of the sonic hedgehog-vegf-notch signaling cascade that controls arterial/venous fate. ..
- Sung J, Jeon J, Lee J, Kim C. Zebrafish Jak2a plays a crucial role in definitive hematopoiesis and blood vessel formation. Biochem Biophys Res Commun. 2009;378:629-33 pubmed publisher..Thus, our data indicate that zebrafish Jak2a is important in both definitive hematopoiesis and blood vessel formation. ..
- Germana A, Marino F, Guerrera M, Campo S, De Girolamo P, Montalbano G, et al. Expression and distribution of S100 protein in the nervous system of the adult zebrafish (Danio rerio). Microsc Res Tech. 2008;71:248-55 pubmed
- He X, Yan Y, Eberhart J, Herpin A, Wagner T, Schartl M, et al. miR-196 regulates axial patterning and pectoral appendage initiation. Dev Biol. 2011;357:463-77 pubmed publisher..These results show that a Hox cluster microRNA modulates development of axial patterning similar to nearby protein-coding Hox genes, and acts on appendicular patterning at least in part by modulating retinoic acid signaling. ..
- Daroczi B, Kari G, Ren Q, Dicker A, Rodeck U. Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos. Mol Cancer Ther. 2009;8:2625-34 pubmed publisher..In conclusion, inhibitors of canonical pathways to NF-kappaB activation may be useful in alleviating radiation toxicity in patients. ..
- Klaassen L, Sun Z, Steijaert M, Bolte P, Fahrenfort I, Sjoerdsma T, et al. Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels. PLoS Biol. 2011;9:e1001107 pubmed publisher..This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina. ..
- Xiong X, Dong C, Xu X, Weng S, Liu Z, He J. Proteomic analysis of zebrafish (Danio rerio) infected with infectious spleen and kidney necrosis virus. Dev Comp Immunol. 2011;35:431-40 pubmed publisher..These findings provide insight into the interactions between iridoviruses (especially ISKNV) and host, as well as the mechanism and pathogenesis of ISKNV infections. ..
- Burket C, Montgomery J, Thummel R, Kassen S, LaFave M, Langenau D, et al. Generation and characterization of transgenic zebrafish lines using different ubiquitous promoters. Transgenic Res. 2008;17:265-79 pubmed..For these reasons, these four promoters will be valuable tools for expressing transgenes in adult zebrafish. ..
- Saul K, Koke J, Garcia D. Activating transcription factor 3 (ATF3) expression in the neural retina and optic nerve of zebrafish during optic nerve regeneration. Comp Biochem Physiol A Mol Integr Physiol. 2010;155:172-82 pubmed publisher..We conclude ATF3 may be an important mediator of optic nerve regeneration-promoting gene expression in fish, a role which merits further investigation. ..
- Grimes A, Erwin K, Stadt H, Hunter G, Gefroh H, Tsai H, et al. PCB126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development. Toxicol Sci. 2008;106:193-205 pubmed publisher..HLHS is a severe congenital cardiovascular malformation that has previously been linked to industrial releases of dioxins and PCBs. ..
- Tsalavouta M, Astudillo O, Byrnes L, Nolan C. Regulation of expression of zebrafish (Danio rerio) insulin-like growth factor 2 receptor: implications for evolution at the IGF2R locus. Evol Dev. 2009;11:546-58 pubmed publisher..We propose that evolution of imprinting at the mammalian IGF2R may have facilitated the loss of negative regulation of translation conferred by uAUGs. ..
- Tiso N, Filippi A, Benato F, Negrisolo E, Modena N, Vaccari E, et al. Differential expression and regulation of olig genes in zebrafish. J Comp Neurol. 2009;515:378-96 pubmed publisher..Our findings suggest a role for olig genes in CNS patterning as well as in multiple cell fate decisions during neural differentiation. ..
- Yang H, Xiang J, Wang N, Zhao Y, Hyman J, Li S, et al. Converse conformational control of smoothened activity by structurally related small molecules. J Biol Chem. 2009;284:20876-84 pubmed publisher..Our study represents the first demonstration of conformational regulation of Smo by small molecule analogs, and the combinational use of these Smo modulators in a temporal controlled fashion should be useful for studying Hh biology. ..
- Glinka M, Herrmann T, Funk N, Havlicek S, Rossoll W, Winkler C, et al. The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal beta-actin mRNA translocation in spinal motor neurons. Hum Mol Genet. 2010;19:1951-66 pubmed publisher..Our data suggest that hnRNP-R-mediated axonal beta-actin mRNA translocation plays an essential physiological role for axon growth and presynaptic differentiation. ..
- Rosemberg D, Rico E, Guidoti M, Dias R, Souza D, Bonan C, et al. Adenosine deaminase-related genes: molecular identification, tissue expression pattern and truncated alternative splice isoform in adult zebrafish (Danio rerio). Life Sci. 2007;81:1526-34 pubmed..These findings demonstrated the existence of different ADA-related genes, their distinct expression pattern and a truncated ADA2-1 isoform, which suggest a high degree of complexity in zebrafish adenosinergic system. ..
- Wang Z, Zhang S, Wang G. Response of complement expression to challenge with lipopolysaccharide in embryos/larvae of zebrafish Danio rerio: acquisition of immunocompetent complement. Fish Shellfish Immunol. 2008;25:264-70 pubmed publisher..Taken together, these suggest that the complement operating via the AP is already competent by responding to challenge with LPS in the hatched larvae of Danio rerio. ..
- Jin Y, Chen R, Sun L, Wang W, Zhou L, Liu W, et al. Enantioselective induction of estrogen-responsive gene expression by permethrin enantiomers in embryo-larval zebrafish. Chemosphere. 2009;74:1238-44 pubmed publisher..These findings add to a growing body of evidence concerning enantioselectivity in the toxicity, endocrine-disrupting activity, and environmental biodegradation of chiral pesticides. ..
- Zhong H, Li Z, Lin S, Chang Y. Initiation of V(D)J recombination in zebrafish (Danio rerio) ovaries. Mol Immunol. 2007;44:1784-92 pubmed..Our data, therefore, substantiate the speculation that RAG might have been derived from a transposase, invading germ cells of ancient species, and later become a dedicated recombinase only expressed in developing lymphocytes. ..
- Shankaran S, Capell A, Hruscha A, Fellerer K, Neumann M, Schmid B, et al. Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem. 2008;283:1744-53 pubmed..Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease-characterizing C-terminal fragments could be observed. ..
- Lepiller S, Franche N, Solary E, Chluba J, Laurens V. Comparative analysis of zebrafish nos2a and nos2b genes. Gene. 2009;445:58-65 pubmed publisher..Thus, the evolution of nos2 genes in zebrafish provides a typical example of gene divergence after duplication. ..
- Reschly E, Bainy A, Mattos J, Hagey L, Bahary N, Mada S, et al. Functional evolution of the vitamin D and pregnane X receptors. BMC Evol Biol. 2007;7:222 pubmed..In addition, several assays were used to search for evidence of PXR-mediated hepatic effects in three model non-mammalian species: sea lamprey (Petromyzon marinus), zebrafish (Danio rerio), and African clawed frog (Xenopus laevis)...
- Rico E, Rosemberg D, Senger M, de Bem Arizi M, Dias R, Souto A, et al. Ethanol and acetaldehyde alter NTPDase and 5'-nucleotidase from zebrafish brain membranes. Neurochem Int. 2008;52:290-6 pubmed
- Duffy K, McAleer M, Davidson W, Kari L, Kari C, Liu C, et al. Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids. Nucleic Acids Res. 2005;33:4914-21 pubmed
- Bai X, Kim J, Yang Z, Jurynec M, Akie T, Lee J, et al. TIF1gamma controls erythroid cell fate by regulating transcription elongation. Cell. 2010;142:133-43 pubmed publisher..Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation. ..
- Kochilas L, Potluri V, Gitler A, Balasubramanian K, Chin A. Cloning and characterization of zebrafish tbx1. Gene Expr Patterns. 2003;3:645-51 pubmed..This newly identified tbx1 expression pattern in cardiac regions other than the cardiac outflow tract offers a new insight into the role of the tbx1 transcription factor in cardiac development. ..
- Gonzalez P, Dominique Y, Massabuau J, Boudou A, Bourdineaud J. Comparative effects of dietary methylmercury on gene expression in liver, skeletal muscle, and brain of the zebrafish (Danio rerio). Environ Sci Technol. 2005;39:3972-80 pubmed..The expression of the metallothionein mt2 and the DNA repair rad51 genes was up-regulated in liver between 21 and 63 days, whereas in skeletal muscle, mt2 remained uninduced, and gadd and rad51 were found to be repressed. ..
- Bree R, McLoughlin S, Jin S, McMeel O, Stainier D, Grealy M, et al. nanor, a novel zygotic gene, is expressed initially at the midblastula transition in zebrafish. Biochem Biophys Res Commun. 2005;333:722-8 pubmed..It is initially expressed after the MBT at the sphere stage and during epiboly it is expressed in the forerunner cells. At 24 h post-fertilization, expression is solely anterior. ..
- van Aerle R, Kille P, Lange A, Tyler C. Evidence for the existence of a functional Kiss1/Kiss1 receptor pathway in fish. Peptides. 2008;29:57-64 pubmed..This is the first report of the existence and characterization of the Kiss1 gene outside the mammalian taxa, suggesting that a functional Kiss1/Kiss1 receptor pathway is conserved across vertebrate species. ..
- McGrail M, Hatler J, Kuang X, Liao H, Nannapaneni K, Watt K, et al. Somatic mutagenesis with a Sleeping Beauty transposon system leads to solid tumor formation in zebrafish. PLoS ONE. 2011;6:e18826 pubmed publisher..The zebrafish T2/OncZ cancer model will be useful for identifying novel and conserved genetic drivers of human cancers. ..
- Barrallo A, Gonzalez Sarmiento R, García Isidoro M, Cidad P, Porteros A, Rodriguez R. Differential brain expression of a new beta-actin gene from zebrafish (Danio rerio). Eur J Neurosci. 1999;11:369-72 pubmed..Our results suggest that in adult brain zebrafish, this new gene is expressed during neuronal cell proliferation. ..
- Pei D, Sun Y, Chen S, Wang Y, Hu W, Zhu Z. Zebrafish GAPDH can be used as a reference gene for expression analysis in cross-subfamily cloned embryos. Anal Biochem. 2007;363:291-3 pubmed
- Marques I, Leito J, Spaink H, Testerink J, Jaspers R, Witte F, et al. Transcriptome analysis of the response to chronic constant hypoxia in zebrafish hearts. J Comp Physiol B. 2008;178:77-92 pubmed..We have identified here many novel genes involved in the response to CCH in the heart, which may have potential clinical implications in the future. ..
- Jin Y, Wang W, Sheng G, Liu W, Fu Z. Hepatic and extrahepatic expression of estrogen-responsive genes in male adult zebrafish (Danio rerio) as biomarkers of short-term exposure to 17beta-estradiol. Environ Monit Assess. 2008;146:105-11 pubmed..These results suggest that Vtg I mRNA is a highly sensitive biomarker for determining the estrogenic effects of E2 and that the skin of zebrafish may be an appropriate substitute for liver for such a determination. ..
- Dos Anjos N, Schulze T, Brack W, Val A, Schirmer K, Scholz S. Identification and evaluation of cyp1a transcript expression in fish as molecular biomarker for petroleum contamination in tropical fresh water ecosystems. Aquat Toxicol. 2011;103:46-52 pubmed publisher..The data demonstrate the high sensitivity of cyp1a as indicator of oil exposure; further studies should be considered to test its usefulness at known contaminated sites and to evaluate influential factors by, e.g. mesocosm experiments...
- Lin C, Yang P, Kao C, Huang H, Tsai H. Transgenic zebrafish eggs containing bactericidal peptide is a novel food supplement enhancing resistance to pathogenic infection of fish. Fish Shellfish Immunol. 2010;28:419-27 pubmed publisher..2%). This line of evidence suggested that pathogen resistance can be enhanced by using transgenic embryos containing LFB-GFP as a food supplement for fish, while, at the same time, reducing the demand of chemical antibiotics. ..
- Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty K, Lawson N. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature. 2010;464:1196-200 pubmed publisher..Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signalling in endothelial cells to guide angiogenesis. ..
- Bartman T, Walsh E, Wen K, McKane M, Ren J, Alexander J, et al. Early myocardial function affects endocardial cushion development in zebrafish. PLoS Biol. 2004;2:E129 pubmed
- Sandrini J, Trindade G, Nery L, Marins L. Time-course expression of DNA repair-related genes in hepatocytes of zebrafish (Danio rerio) after UV-B exposure. Photochem Photobiol. 2009;85:220-6 pubmed publisher..In conclusion, these results demonstrate an activation of the DNA repair system in hepatocytes of zebrafish exposed to UV-B radiation, mainly involving the participation of p53. ..
- Besser J, Leito J, van der Meer D, Bagowski C. Tip-1 induces filopodia growth and is important for gastrulation movements during zebrafish development. Dev Growth Differ. 2007;49:205-14 pubmed..Our observations indicate a role for TIP-1 in gastrulation movements and in filopodia growth induction. ..
- Lerebours A, Adam Guillermin C, Brèthes D, Frelon S, Floriani M, Camilleri V, et al. Mitochondrial energetic metabolism perturbations in skeletal muscles and brain of zebrafish (Danio rerio) exposed to low concentrations of waterborne uranium. Aquat Toxicol. 2010;100:66-74 pubmed publisher..These effects were largest at the lowest concentration, following 28 days of exposure. ..
- Voelker D, Vess C, Tillmann M, Nagel R, Otto G, Geisler R, et al. Differential gene expression as a toxicant-sensitive endpoint in zebrafish embryos and larvae. Aquat Toxicol. 2007;81:355-64 pubmed..This study therefore indicates that gene expression analysis in DarT is able to reveal mechanistic information and may also be exploited for the development of replacement methods for chronic fish tests. ..
- Deng J, Yu L, Liu C, Yu K, Shi X, Yeung L, et al. Hexabromocyclododecane-induced developmental toxicity and apoptosis in zebrafish embryos. Aquat Toxicol. 2009;93:29-36 pubmed publisher..The results also indicate that zebrafish embryos can serve as a reliable model for the developmental toxicity of HBCD. ..
- Lerebours A, Gonzalez P, Adam C, Camilleri V, Bourdineaud J, Garnier Laplace J. Comparative analysis of gene expression in brain, liver, skeletal muscles, and gills of zebrafish (Danio rerio) exposed to environmentally relevant waterborne uranium concentrations. Environ Toxicol Chem. 2009;28:1271-8 pubmed publisher..During the depuration phase, uranium excretion was inefficient in brain and skeletal muscles, and expression of most of the tissue-specific genes was repressed or unchanged. ..
- Behrendt L, Jönsson M, Goldstone J, Stegeman J. Induction of cytochrome P450 1 genes and stress response genes in developing zebrafish exposed to ultraviolet radiation. Aquat Toxicol. 2010;98:74-82 pubmed publisher..The results show that UVB can induce expression of CYP1 genes as well stress response genes in developing zebrafish, and that UVB intensity and duration influence the responses. ..
- Rico E, Rosemberg D, Senger M, Arizi M, Bernardi G, Dias R, et al. Methanol alters ecto-nucleotidases and acetylcholinesterase in zebrafish brain. Neurotoxicol Teratol. 2006;28:489-96 pubmed..0% (29.2%). Nevertheless, AMP hydrolysis and AChE were not altered after in vitro exposure. The inhibitory effect observed on these enzymes could contribute to the neurodegenerative events promoted by methanol in zebrafish brain. ..
- Mo S, Song P, Lv D, Chen Y, Zhou W, Gong W, et al. Zebrafish z-otu, a novel Otu and Tudor domain-containing gene, is expressed in early stages of oogenesis and embryogenesis. Biochim Biophys Acta. 2005;1732:1-7 pubmed..Therefore, z-otu might link the ubiquitin signaling pathway to early oogenesis and maintaining the totipotency of embryonic cell. ..
- McClelland G, Craig P, Dhekney K, Dipardo S. Temperature- and exercise-induced gene expression and metabolic enzyme changes in skeletal muscle of adult zebrafish (Danio rerio). J Physiol. 2006;577:739-51 pubmed..e. CS and PPAR-beta1 mRNA) that contribute to specific temperature- and exercise-induced phenotypes. ..
- Thummel R, Li L, Tanase C, Sarras M, Godwin A. Differences in expression pattern and function between zebrafish hoxc13 orthologs: recruitment of Hoxc13b into an early embryonic role. Dev Biol. 2004;274:318-33 pubmed..The extent of the delay does not change through 20 hpf; however, an additional delay emerges at this time. Notably, this second phase of the delay correlates with hoxc13b expression pattern becoming restricted to the tail bud. ..
- Van Raay T, Fortino N, Miller B, Ma H, Lau G, Li C, et al. Naked1 antagonizes Wnt signaling by preventing nuclear accumulation of ?-catenin. PLoS ONE. 2011;6:e18650 pubmed publisher..Given the conserved nature of Nkd1, our results shed light on the negative feedback regulation of Wnt signaling through the Nkd1-mediated negative control of nuclear accumulation of ?-catenin. ..
- Gonzalez P, Baudrimont M, Boudou A, Bourdineaud J. Comparative effects of direct cadmium contamination on gene expression in gills, liver, skeletal muscles and brain of the zebrafish (Danio rerio). Biometals. 2006;19:225-35 pubmed..Then, after 21 days, the expression of almost every genes returned to basal levels while both mt1 and mt2 genes were up-regulated. ..
- Liu Y, Wang J, Wei Y, Zhang H, Xu M, Dai J. Induction of time-dependent oxidative stress and related transcriptional effects of perfluorododecanoic acid in zebrafish liver. Aquat Toxicol. 2008;89:242-50 pubmed publisher..These results demonstrate that turbulence of fatty acid beta-oxidation and oxidative stress responses were involved in the PFDoA-induced hepatotoxicity. ..