title: [Drug-induced Nonalcoholic Steatohepatitis].
abstract: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease characterized by intense liver steatosis accompanied by hepatocyte destruction, inflammation and fibrous, despite little or no history of alcoholic consumption. There are also cases of drug-induced secondary steatohepatitis. Drug-induced steatohepatitis is a relatively rare type of drug-induced liver disease, but close attention to the possible onset of steatohepatitis is needed when drugs with the potential to induce fatty liver are prescribed for long term use. Estrogen is a factor indispensable to smooth fatty acid β-oxidation in hepatocytes. However, treatment with Tamoxifen markedly suppresses fatty acid β-oxidation in the liver. As free fatty acids are toxic, their accumulation results in the activation of alternative fatty acid oxidation pathways mediated by CYP2E1 in cytosol and lipid peroxidases in peroxisomes in hepatocytes. CYP2E1 enhances lipid peroxidation and dicarboxylic acid synthesis via the activation of fatty acid ω-oxidation that injures mitochondria and results in the emergence of ballooned hepatocytes. In such cases, the attenuation of alternative fatty acid oxidation pathways could have some beneficial effects on mitochondrial injury, since fibrates (PPAR-α ligands) are potent enough to stimulate neutral fat consumption through the activation of peroxisomal fatty acid β-oxidation. Fortunately, fibrates attenuate serum estrogen levels by affecting estrogen receptor expression, so the co-administration of fibrates with Tamoxifen is expected to exert higher efficacy in breast cancer patients with Tamoxifen-induced hepatic steatosis.
authors.affiliation: Department of Pharmacy, Kochi Medical School Hospital.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Miyamura
authors.forename: Junko
authors.initials: J
authors.lastname: Yokota
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D004965:Estrogen Antagonists / Q000009:adverse effects*; D004967:Estrogens / Q000097:blood / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D058607:Fibric Acids / Q000008:administration & dosage / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000517:prevention & control; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D004967:Estrogens; D005227:Fatty Acids; D058607:Fibric Acids; D013629:Tamoxifen; D019392:Cytochrome P-450 CYP2E1