Inactivation of Carcinogenic Diol Epoxides of Dibenzo[ a,l ]pyrene (Dibenzo[ def,p ]chrysene) by Human Alpha Class Glutathione Transferases

Abstract

Human Alpha class glutathione transferases (hGSTs) have been incubated with the ultimate carcinogenic ( m )- anti - and (+)- syn -diol epoxides (DE) of the nonplanar dibenzo[ a,l ]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 ( m )- anti enantiomer with hGSTA1-1 as the most efficient enzyme (k cat /K M = 464 mM m 1 s m 1 ) followed by A3-3 and A2-2 (k cat /K M = 190 mM m 1 s m 1 and 30.4 mM m 1 s m 1 , respectively). With ( m )- anti -DBPDE, the k cat /K M values were in general about 10-fold lower. Replacing ( m )- anti -DBPDE with the less complex ( m )- 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.