Inactivation of carcinogenic diol epoxides of dibenzo[a,l]pyrene (dibenzo[def,p]chrysene) by human alpha class glutathione transferases

Human Alpha class glutathione transferases (hGSTs) have been incubated with the ultimate carcinogenic (-)-anti- and (+)-syn-diol epoxides (DE) of the nonplanar dibenzo[a,1]pyrene (DBP). hGSTA1-1, A2-2, and A3-3 demonstrate activity with both diol epoxides (R-absolute configuration at the benzylic oxirane carbon) whereas hGSTA4-4 virtually was inactive. (+)-syn-DBPDE was superior as substrate compared to the (-)-anti enantiomer with hGSTA1-1 as the most efficient enzyme (k(cat)/K-M = 464 mM(-1)s(-1))followed by A3-3 and A2-2 (k(cat)/K-M = 190 mM(-1)s(-1) and 30.4 mM(-1) s(-1), respectively). With (-)-anti-DBPDE, the k(cat)/K-M values were in general about 10-fold lower. Replacing (-)-anti-DBPDE vith the less complex (-)-anti-BCDE or the less structurally distorted (+)-anti-BPDE, revealed that GSTA1-1 was 19- and 25-fold less active, respectively. hGSTA1-1 is present in human lung, a primary target tissue for PAH-induced tumors. Considering the great efficiency of this isoform relative to both Pi and Mu-class GSTs toward DBPDE, its presence and extent of expression may play a significant role in protection against this type of highly carcinogenic, compounds.