Mouse strain differences in glutathione S-transferase activity and aflatoxin B 1 biotransformation

Abstract

Previous studies have suggested that mice are resistant to the carcinogenic effects of aflatoxin B 1 (afb 1) and that this resistance is largely the result of expression of an isoenzyme of glutathione S-transferase (GST) with high activity toward AFB 1-8,9-epoxide. Significant interstrain differences in cytosolic GST activities toward a variety of substrates have been reported in mice. If such differences exist for the conjugation of AFB 1-8,9-epoxide, then there may be significant mouse strain differences in susceptibility to afb 1-induced hepatocarcinogenicity. The hepatic microsomal and cytosolic biotransfonnation of afb 1 was studied in 8 different strains of mice fed a purified diet. GST-mediated conjugation of AFB 1-8,9-epoxide with glutathione and GST activity toward l-chloro-2,4-dinitrobenzene (CDNB), l,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (ECA) and cumene hydroperoxide (CHP) were determined with cytosolic fractions from 8–10 pooled livers. Specific activities of cytochrome-P-450-mediated oxidation of AFB 1 to aflatoxin Q 1 (AFQ 1), aflatoxin m 1 (AFM 1), and aflatoxin p 1 (AFP 1), as well as the reactive intermediate AFB 1-8,9-epoxide, were determined with hepatic microsomal fractions from each mouse strain. No striking differences in specific activity between mouse strains were observed for any of the P-450- or GST-mediated enzymatic pathways measured, although some statistically significant differences were found. GST specific activities toward AFB 1-8,9-epoxide, CDNB, DCNB, ECA and CHP ranged from 1.5–2.1, 2,830–5,370, 81–144, 38–69 and 32–73 nmol/mg protein/min, respectively. The rate of formation of AFB 1-8,9-epoxide ranged from 208 to 465 pmol/mg protein/min. The specific activities of AFQ 1,AFM 1, and AFP 1 formation by microsomes ranged from 36–70, 161–326, and 252–426 pmol/mg protein/min, respectively. Mice fed a standard rodent chow diet showed evidence of microsomal and cytosolic enzyme induction when compared to mice fed a purified diet. The lack of substantial differences in enzyme specific activities between mouse strains suggests that interstrain variations in the hepatocarcinogenic effects of AFB 1 in mice should not be large.