The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity.
Amiodarone is a widely used potent antiarrhythmic for the treatment of cardiac disease; however, its use is often discontinued due to numerous adverse effects, including hepatotoxicity. To investigate the role of drug metabolism in this liver toxicity, amiodarone and its major metabolite desethylamiodarone were incubated with HepG2 cells overexpressing a series of cytochrome P450 (CYP) isoforms. Significantly higher cytotoxicity of amiodarone was observed in HepG2 cells overexpressing CYP3A4 or CYP1A1, compared with that observed in empty vector transduced control cells. Further, higher levels of the more potent hepatotoxic metabolite desethylamiodarone were detected in CYP3A4 or CYP1A1 expressed cells. The CYP3A4 inhibitor ketoconazole and the CYP1A1 inhibitor α-naphthoflavone drastically inhibited the metabolism of amiodarone to desethylamiodarone. Along with the inhibition of CYP1A1 or CYP3A4, the cytotoxicity of amiodarone was significantly reduced. These data indicate that the metabolism of amiodarone to desethylamiodarone by CYP1A1 or CYP3A4 plays an important role in the hepatocellular toxicity of amiodarone.
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Qiangen
Q
Wu
Division of System Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Baitang
B
Ning
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Jiekun
J
Xuan
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Zhen
Z
Ren
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Lei.Guo@fda.hhs.gov.
Lei
L
Guo
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Matthew.Bryant@fda.hhs.gov.
Matthew S
MS
Bryant
D065767:Activation, Metabolic; D000638:Amiodarone / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D001571:Benzoflavones; D065692:Cytochrome P-450 CYP3A Inhibitors; C011512:alpha-naphthoflavone; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C036116:desethylamiodarone; D000638:Amiodarone; D007654:Ketoconazole
Amiodarone; Amiodarone metabolism; Cytochrome P450s (CYPs); Desethylamiodarone; HepG2 cells; HepG2 expressing CYP