GENDER-RELATED DIFFERENCES IN SUSCEPTIBILITY OF A J MOUSE TO BENZO[A]PYRENE-INDUCED PULMONARY AND FORESTOMACH TUMORIGENESIS/

Benzo[a]pyrene (BP) is a suspected human carcinogen and is known to pr oduce tumors in the lung and forestomach of mice. Glutathione (GSH) S- transferases (GST) play a major role in the detoxification of the ulti mate carcinogen of BP, (+)-anti-7,8-dihydroxy-9, 10-oxy-7,8,9,10-tetra hydrobenzo[a]pyrene ((+)-anti-BPDE). Previous studies have shown gende r related differences in the expression of GST isoenzymes in mice. The present study was designed to test the hypothesis whether gender-rela ted differences in the expression of GST isoenzymes can affect the sus ceptibility of mice to BP-induced lung and forestomach tumorigenesis. The expression of pi class isoenzyme mGSTP1-1, which is highly efficie nt in the detoxification of (+)-anti-BPDE, was approximately 3,0- and 1.5-fold higher in the liver and forestomach of male A/J mouse, respec tively, as compared with the female. The levels of other major GST iso enzymes, mGSTA3-3 (cr class), mGSTM1-1 (mu class) and mGSTA4-4 (alpha class), were also significantly higher in the liver of the male mouse as compared with the female. While pulmonary mGSTP1-1 expression did n ot differ significantly between male and female A/J mice, the expressi on of mGSTA3-3, mGSTM1-1 and mGSTA4-4 was significantly higher (1.4-4. 0-fold) in the lung of the male A/J mouse as compared with the female. At lower concentrations of BP (0.5 mg BP/mouse), the tumor incidence/ multiplicity was significantly higher in the lung as well as in the fo restomach of female mice as compared with male mice. For example, whil e 30% of the female mice developed pulmonary tumors 26 weeks after the first 0.5 mg BP administration, none of the male mice had tumors in t heir lungs. At higher doses of BP (1.5 mg BP/mouse), however, this dif ferential was either abolished or relatively less pronounced. Our resu lts suggest that up to a certain threshold of BP exposure the levels o f GST isoenzymes may be an important determinant of susceptibility to BP-induced tumorigenesis in mice. (C) 1998 Elsevier Science Ireland Lt d. All rights reserved.