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Effect of Sex Difference on the in Vitro and in Vivo Metabolism of Aflatoxin B₁ by the Rat¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

Hepatic microsome-catalyzed metabolism of aflatoxin B₁ (AFB₁) to aflatoxin M₁ and aflatoxin Q₁ and the "metabolic activation" of AFB₁ to DNA-alkylating metabolite(s) were studied in normal male and female Sprague-Dawley rats, in gonadectomized animals, and in castrated males and normal females treated with testosterone. Microsomes from male animals formed 2 to 5 times more aflatoxin M₁, aflatoxin Q₁, and DNA-alkylating metabolite(s) than those from females. Castration reduced the metabolism of AFB₁ by the microsomes from males by about 50%, whereas ovariectomy had no significant effect on AFB₁ metabolism by the microsomes from females. Testosterone treatment (4 mg/rat, 3 times/week for about 6 weeks) of castrated immature males and immature females enhanced the metabolism of AFB₁ by their microsomes. A sex difference in the metabolism of AFB₁ by liver microsomes was also seen in other strains of rats tested: Wistar, Long-Evans, and Fischer. The activity of kidney microsomes for metabolic activation was 1 to 4% that of the liver activity and was generally lower in microsomes from male rats as compared to those from female rats of Sprague-Dawley, Wistar, and Long-Evans strains. The in vitro results obtained with hepatic microsomes correlated well with the in vivo metabolism of AFB₁, in that more AFB₁ became bound in vivo to hepatic DNA isolated from male rats and from a female rat treated with testosterone than that isolated from control female rats. These data suggest that the differences in hepatic AFB₁ metabolism may be the underlying cause of the sex difference in toxicity and carcinogenicity of AFB₁ observed in rats.

¹ This work was supported by USPHS Grants ES-00993 and CA-13038.

² To whom requests for reprints should be addressed.

Received 5/26/76. Accepted 9/13/76.