Metabolism of nicergoline (Sermion), An ergot derivative active in senile mental impairment, In rat brain

An in vitro mammalian assay system has been used to examine the importance of specific enzymes and/or enzyme ratios in the metabolic toxification/detoxification of benzo[a]pyrene (BP). The assay incorporates the postmitochondrial supernatant (S15 fraction) prepared from a rat liver homogenate as an enzyme source and V79 Chinese hamster cells as targets for chemically induced damage. In order to determine the importance of specific enzymes in the metabolic activation of benzo[a]pyrene in vitro, the enzyme pattern in the S15 fraction was modulated by pretreating the experimental animals with enzyme inducers and/or by adding enzyme inhibitors in vitro. The enzyme activity (ethoxyresorufin-O-deethylase (EROD), a measure of 3-methylcholanthrene-inducible mixed function oxidases; ethyl-morphine-N-demethylase (EMND), a measure of phenobarbital-inducible mixed function oxidases; and epoxide hydrase (EH)) in a given S15 fraction was determined, and the ability of the preparation to induce mutagenicity and / or cytotoxicity in the presence of BP was assessed. Correlations were made between the activity of a particular enzyme or enzyme ratio in the S15 fraction and the biological response produced by BP, i.e. cytotoxicity and mutagenicity.When the role of individual enzymes was evaluated, EH, but not EROD or EMND, correlated (p < 0.01) with the degree of BP-induced cytotoxicity and mutagenicity. As EH activity in the S15 fraction increased, the degree of cytotoxicity and mutagenicity observed as a result of metabolism decreased. When enzyme ratios were evaluated, we found two significant (P < 0.01) correlations; EMND/EH and EROD/EH. As these ratios increase, BP becomes more cytotoxic and mutagenic towards V79 cells. Since the adverse biological effects of BP are mediated via epoxides, these results suggest that the experimental approach described in this report will allow one to evaluate the relative importance of various enzymes and/or enzyme patterns in the metabolic toxification/detoxification of other potentially toxic chemicals.