Polycyclic aromatic hydrocarbons (PAHs) represent an important class of carcinogenic contaminants in the aquatic environment. Among the more potent PAHs, methylated PAHs are of particular interest because they are often more mutagenic and carcinogenic than their parent hydrocarbons. Although much is known about the metabolic pathways of methylated PAHs in mammalian systems, no data is available on the metabolism of such compounds in fish. It is well recognized that PAHs require metabolic activation to chemically reactive forms before exerting their carcinogenic effects. PAHs and/or some of their metabolites may persist in fish, be consumed by humans and then be metabolically activated into ultimate carcinogens in human tissues. Therefore, it is important to have information on the metabolic fate of PAHs in fish in order to assess the carcinogenic potential of these chemicals in these organisms as well as the risk to humans who consume the fish. It has been shown that both the regio- and stereoselectivity of the microsomal enzymes involved in the metabolic activation of PAHs play a major role in determining the carcinogenicity of these chemicals. Examination of the metabolic pathways of methylated PAHs in fish is, therefore, important in view of the fact that hepatic microsomal enzymes in fish and rat species exhibit different regioselectivity in the metabolism of PAHs. We propose to investigate the metabolism of 5-methylchrysene (5-MeC) as a model compound to study the metabolism of methylated PAHs by fish. 5-MeC was selected for this study because of its high potency and unique structural features. Of all methylated chrysenes, it is the only isomer which fulfills the postulated structural requirements favoring tumorigenicity in methylated PAHs. The proposed study will also provide information on the ability of fish microsomes to hydroxylate the methyl group, a pathway which has not been previously investigated in fish.
The specific aims of the proposed research are: (1) to elucidate the regio- and stereoselectivity of the liver microsomal enzymes of control and 3-MC treated brown bullhead (a fish species known to be susceptible to the hepatocarcinogenic action of PAHs); (2) to conduct parallel studies as above with chrysene to assess the influence of methyl substitution on the metabolism of the parent hydrocarbon; and (3) to compare the data on the regio- and stereoselective metabolism of 5-MeC by fish liver microsomes with the data published for rat liver microsomes. The long term objective of the proposed research is to obtain a better understanding of the metabolic pathways of PAHs in fish with particular emphasis on the effect of methyl substitution.
| Shappell, Nancy W; Carlino-MacDonald, Uli; Amin, Shantu et al. (2003) Comparative metabolism of chrysene and 5-methylchrysene by rat and rainbow trout liver microsomes. Toxicol Sci 72:260-6 |
