Effect of particulates on metabolism and mutagenicity of benzo[a]pyrene.
Mechanisms of co-carcinogenicity of particulates, such as iron oxide and asbestos, and benzo[a]pyrene (B[a]P) are not completely understood. Particulates dramatically alter rates of uptake of B[a]P into membranes, a factor which could account for co-carcinogenicity. However, B[a]P must be activated to reactive forms to be carcinogenic and mutagenic so alterations in metabolism of B[a]P by particulates also could result in co-carcinogenesis. To elucidate mechanisms of particulate-B[a]P co-carcinogenesis, we have correlated rates of uptake of B[a]P into microsomes with metabolism of B[a]P and with mutagenicity of B[a]P in the Ames test. In general, aryl hydrocarbon hydroxylase (AHH) activity paralleled rates of uptake of B[a]P, though some inhibition of AHH activity by particulates which was not attributable to availability of B[a]P was evident. This inhibition was studied further by assaying separately mixed function oxidase and epoxide hydrase activities in the presence of particulates. Both chrysotile and iron oxide inhibited O-deethylation of 7-ethoxyresorufin and hydration of B[a]P-4,5-oxide. To determine effects of this inhibition on activation of B[a]P to reactive forms, we studied profiles of metabolites of B[a]P and mutagenicity of B[a]P. The only alteration in profiles of B[a]P metabolites produced by particulates was that due to effects on rates of uptake. Similarly, mutagenicity of B[a]P was positively correlated with rates of uptake into microsomes. We conclude that the predominant effects of chrysotile and iron oxide are in altering rates of uptake of particle-adsorbed B[a]P. Changes in uptake rates then result in alterations of B[a]P metabolism and mutagenicity.
D000327:Adsorption; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001194:Asbestos / Q000494:pharmacology*; D017632:Asbestos, Serpentine; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000494:pharmacology; D003460:Crystallization; D004851:Epoxide Hydrolases / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009152:Mutagenicity Tests; D051381:Rats; D011919:Rats, Inbred Strains
D017632:Asbestos, Serpentine; D005290:Ferric Compounds; D001194:Asbestos; C000499:ferric oxide; D001564:Benzo(a)pyrene; D007501:Iron; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D004851:Epoxide Hydrolases