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Species Susceptibility to Aflatoxin B₁ Carcinogenesis: Comparative Kinetics of Microsomal Biotransformation¹

Department of Environmental Health, University of Washington, Seattle, Washington 98195

The biotransformation of the potential human carcinogen aflatoxin B₁ (AFB₁) was studied using hepatic microsomes from the rat, mouse, monkey, and human. Initial rates of AFB₁ oxidation to aflatoxins Q₁, M₁, and P₁, as well as the reactive intermediate AFB₁-8,9-epoxide, were determined using a high performance liquid chromatography assay. The rates of generation of these AFB₁ metabolites were investigated at low substrate concentrations (more representative of environmental exposures) and also at high ("saturating") concentrations commonly utilized in studies in vitro. Striking differences in ratios of the metabolites were observed. At an AFB₁ concentration of 124 µM, mouse and monkey microsomes had the highest rates of AFB₁-8,9-epoxide formation. Primate liver microsomes formed aflatoxin Q₁ in large amounts but failed to produce detectable aflatoxin P₁. Determination of the rates of formation over initial AFB₁ concentrations ranging from 15 to 475 µM revealed that the proportion converted to AFB₁-8,9-epoxide increased at lower substrate concentrations in the case of the rat and human microsomes but not with mouse or monkey microsomes. The differences in patterns of metabolite formation with varying concentrations have implications for interspecies comparisons of carcinogenic potency of AFB₁.

¹ This work was supported by NIH Grants T32 ES-07032, ES-03933, and CA-47561.

² To whom requests for reprints should be addressed, at Department of Environmental Health, SC-34, University of Washington, Seattle, WA 98195.

Received 6/26/89. Revised 10/16/89. Accepted 10/30/89.

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