The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity.

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Wu Q, Ning B, Xuan J, Ren Z, Guo L, Bryant MS

The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity.

Toxicol Lett. 2016 Jun 24;253:55-62. doi: 10.1016/j.toxlet.2016.04.016. Epub 2016 Apr 22.

PubMed ID

27113703 [ View in PubMed

]

Abstract

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 alpha-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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Amiodarone	Cytochrome P450 1A1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Amiodarone Tipranavir	The metabolism of Amiodarone can be decreased when combined with Tipranavir.