Specificity in the Metabolic Activation of Chlorinated Ethylenes by Cytochromes P450 in Primary Rat Hepatocytes

概要

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The manifestation of toxicity by certain environmental compounds requires enzymatic activation. It is well known that chlorinated ethylenes (CEs) are metabolized by intracellular enzymes represented by cytochromes P450 (CYPs) to the urinary secreted forms via epoxide intermediates, which are responsible for their toxicities by forming complexes with intracellular components including CYPs. In order to study the roles of CYPs in the metabolic activation of tetrachloroethylene (PCE), trichloroethylene (TCE) or 1, 1-dichloroethylene (1, 1-DCE), the cytotoxicity of individual CEs were tested in primary hepatocyte cultures established from animals treated with various CYP-inducers such as 3-methylchoranthrene (inducer of CYP1A1/2), phenobarbital (CYP2B1/2) and pyridine (CYP2E1). The cytotoxicity of CEs measured by lactate dehydrogenase leakage after 24 hr was enhanced in different fashions, depending on the CYP inducers used. The results are summarized as follows: CYP1A1/2 and 2B1/2 raised the cytotoxicity of PCE; CYP2B1/2 was exclusively associated with the enhanced cytotoxicity of TCE; and CYP2E1 and 2B1/2 were proved to potentiate 1, 1-DCE. Based on these observations, CEs differing in the number of chlorine substitutions were disclosed to have divergent preferences for CYPs, by which they were metabolically activated.
公益社団法人日本薬学会の論文
2001-02-01