Studies on metabolism and toxicity of styrene part 2 mutagenesis in salmonella typhimurium by metabolic activation of styrene with 3 methyl cholanthrene pre treated rat liver

Watabe, T.; Isobe, M.; Yoshikawa, K.; Takabatake, E.

Journal of Pharmacobio Dynamics 1(5): 301-309


ISSN/ISBN: 0386-846X
Accession: 006509465

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Styrene showed a weak mutagenic activity towards S. typhimurium TA 100 after being activated by the hepatic 9000 g supernatant fraction (S9) obtained from rats pretreated with 3-methylcholanthrene or phenobarbital and fortified with an NADPH-generating system, in the presence of the epoxide hydratase inhibitor, 3,3,3-trichloropropene oxide (TCPO). The 3-methylcholanthrene-pretreated rat liver S9 activated styrene more effectively than the phenobarbital treated one. No mutagenic activity was observed when either TCPO or S9 was omitted. Phenyloxirane, an intermediate in the major metabolic pathway of styrene by hepatic microsomes, induced mutations in TA 100 and TA 1535 cells in the absence of both S9 and TCPO. Analytical data of phenyloxirane and its hydrolytic product, 1-phenyl-1,3-ethanediol, formed in the mutation assay system for styrene indicated that the inducers used for hepatic drug-metabolizing enzymes enhanced both microsomal monooxygenase and epoxide hydratase activities. Relative ratios of the enhanced monooxygenase to hydratase activities were twice as high in 3-methylcholanthrene as the control and 1.8 and 1.2 times in phenobarbital and PCB , respectively, although the last enhanced both activities to the highest extent. Phenyloxirane was accumulated in the presence of TCPO Q in the styrene-activating system most significantly when 3-methylcholanthrene-pretreated rat liver S9 was used. The mutagenicity exerted by the metabolic activation of styrene could not necessarily be explained only by phenyloxirane since sums of both metabolites were smaller than the amount of the epoxide required for inducing the mutation in Salmonella and suggested a possibility of the presence of at least 1 more unknown mutagenic metabolite with an epoxide structure.