PEROXISOMES AND HEPATOTOXICITY

Peroxisomes are ubiquitous organelles of eukaryotic cells and are pres ent in significant amounts in hepatic liver cells. Peroxisomal enzymes contribute to several metabolic pathways including fatty acid, purine and amino acid catabolism or bile acid synthesis. The peroxisomal oxi dative reactions produce hydrogen peroxide, mostly degraded by catalas e which prevents oxidative stress. Moreover, peroxisomes are involved in arylderivative drug detoxification through its epoxide hydrolase ac tivity. In rodents the exposure of cells to xenobiotic compounds such as fibrates, phthalates/adipates and chlorophenoxyacetic acid derivati ves, which are used as hypolipaemic drugs, plasticizers and pesticides respectively, lead to a liver mass increase and to a high peroxisome proliferation. This latter event is due to a strong genetic activation triggered by the PPAR (peroxisome proliferator activated nuclear rece ptor). Human contrasts with rodent since there is no, or little, effec t of the above cited compounds. In contrast, the defect of single or m ultiple peroxisomal functions caused by genetic disorders lead to an i ncrease of very long chain fatty acid level, which is toxic, especiall y for brain and kidney. The liver response to xenobiotics of the perox isome proliferator class may be modulated by auxiliary compounds such as hormones (e.g. thyroid hormone) or nutriments (e.g. retinoids).