Evidence of idiotypic modulation in the immune response to gp43, the major antigenic component of Paracoccidioides brasiliensis in both mice and humans

The kinetics of the glutathione (GSH) conjugation of (+)- and (-)-enantiomers of anti- as well as syn-3,4-dihydroxy-1,2-oxy-1,2,3, 4-tetrahydrobenzoc]phenanthrene (Bc]PDE) catalyzed by murine GSH S-transferase (GST) isoenzymes has been investigated. Murine GSTs exhibited significant differences in their enantioselectivity toward Bc]PDE stereoisomers. For example, while pi class isoenzyme mGSTP1-1 was virtually inactive toward stereoisomers with 1S configuration (-)-syn-and (+)-anti-Bc]PDE], these stereoisomers were good substrates for alpha class isoenzyme mGSTA1-2. When GST activity was measured as a function of varying Bc]PDE concentration (10-320 microM) at a fixed saturating concentration of GSH (2 mM), each isoenzyme examined obeyed Michaelis-Menten kinetics with all four Bc]PDE stereoisomers. Alpha class isoenzyme mGSTA4-4 exhibited negligible activity toward all four stereoisomers of Bc]PDE. The catalytic efficiency of mGSTA1-2 was approximately 1.5- to 15-fold higher than other murine GSTs in the GSH conjugation of (-)-anti-Bc]PDE, which among the four Bc]PDE stereoisomers is the most potent pulmonary carcinogen in the newborn mouse model and a potent skin tumor-initiator. While alpha class isoenzymes mGSTA3-3 and mGSTA1-2 were equally efficient in the GSH conjugation of (+)-anti-Bc]PDE, their catalytic efficiencies toward this stereoisomer were significantly higher than those of mGSTP1-1 and mGSTM1-1. Likewise, mGSTA1-2 was relatively more efficient than other GSTs in the GSH conjugation of both enantiomers of syn-Bc]PDE. In summary, our results indicate that (a) murine GSTs significantly differ in their enantioselectivity in the GSH conjugation of Bc]PDE stereoisomers, which may partially account for the observed differences in the carcinogenic potency of Bc]PDE stereoisomers, and (b) mGSTA1-2 and mGSTA3-3 play a major role in the detoxification of Bc]PDE.