ACTIVITY OF MOUSE-LIVER GLUTATHIONE S-TRANSFERASES TOWARD TRANS,TRANS-MUCONALDEHYDE AND TRANS-4-HYDROXY-2-NONENAL

This study investigated the catalytic activities of hepatic glutathione S-transferase (GST) isoenzymes isolated from CD-1 mice toward two activated alkenals of toxicological relevance: trans,trans-muconaldehyde (MA), a putative myelotoxic metabolite of benzene, and trans-4-hydroxy-2-nonenal (HNE), a highly reactive lipid peroxidation product. The activity toward 1-chloro-2,4-dinitrobenzene (CDNB) was also determined. Four isoenzymes with pI values of 9.8, 8.7, 6.4, and 5.7 were each isolated from male and female mice. The isoenzymes with pI values of 8.7 and 6.4 are π and μ class GSTs, respectively, whereas the pI 9.8 and 5.7 GSTs are both α class isoenzymes. CDNB activity was greatest in the π (pI 8.7) isoenzyme of both sexes. In addition, the CDNB activity of the π (pI 8.7) isoenzyme from males was markedly greater than the corresponding GST from female mouse liver. In contrast to CDNB, both MA and HNE were better substrates for the acidic α (pI 5.7) and μ (pI 6.4) GSTs, whereas minimal activity toward either alkenal was detected in the π (pI 8.7) and α (pI 9.8) isoenzymes. Maximum activity toward MA and HNE was exhibited by the α (pI 5.7) isoenzyme of both sexes. The level of HNE activity observed with the α (pI 5.7) isoenzyme was five- to sixfold greater than that reported previously for any mouse GST isoenzyme. Moreover, the specific activities of the female α (pI 5.7) isoenzyme toward both HNE and MA were markedly greater than those of the corresponding isoenzyme from males. A similar gender-specific difference was noted in the activity of the μ (pI 6.4) isoenzyme toward HNE, but not toward MA. These results show that both MA and HNE are substrates for the α (pI 5.7) and μ (pI 6.4) GSTs of murine liver, with maximum activity toward both activated alkenals exhibited by the α (pI 5.7) isozyme. In addition, evidence is presented that demonstrates a female-dominant sex difference in the activity of the α (pI 5.7) isoenzyme toward MA and HNE, which contrasts sharply with the male-dominant activity of π class GSTs toward CDNB. These results are consistent with the hypothesis that α and μ class GSTs are critical detoxication enzymes in female mouse liver, whereas π-class GST isozymes predominate in the liver of male mice. © 1993 Academic Press. All rights reserved.