INVOLVEMENT OF CYTOCHROME P4502E1 IN THE TOXICITY OF DICHLOROPROPANOLTO RAT HEPATOCYTE CULTURES

Hepatocytes were isolated and cultured from untreated rats and rats tr eated with isoniazid to induce cytochrome P4502E1. Isoniazid selective ly increased p-nitrophenol hydroxylase activity in 2-h cultures, and i ncreased the toxicity of both 1,3- and 2,3-dichloropropanol. Isoniazid also increased the rate and extent of glutathione depletion by the di chloropropanols. There was no effect of isoniazid on the toxicity of 1 ,3-dichloroacetone, precocene II or allyl alcohol. In addition, diethy ldithiocarbamate selectively inhibited p-nitrophenol hydroxylase in 2- h cultures from untreated and isoniazid-treated rats, as well as aboli shing toxicity of the dichloropropanols. In 24-h cultures from isoniaz id-treated rats diethyldithiocarbamate inhibited high affinity MCOD ac tivity by 55% and there was also a small but significant inhibition of precocene II toxicity. These results indicate that isoniazid-inducibl e P4502E1 can mediate the toxicity of dichloropropanol. (C) 1997 Elsev ier Science Ireland Ltd.