Glutathione Conjugation of Bay- and Fjord-Region Diol Epoxides of Polycyclic Aromatic Hydrocarbons by Glutathione Transferases M1-1 and P1-1

Abstract

Metabolism of polycyclic aromatic hydrocarbons in mammalian cells results in the formation of vicinal diol epoxides considered as ultimate carcinogens if the oxirane ring is located in a bay- or fjord-region of the parent compound. In the present study, individual stereoisomers of the bay-region diol epoxides of chrysene, dibenz[a,h]anthracene, and benzo[a]pyrene as well as of the fjord-region diol epoxides of benzo[c]phenanthrene, benzo[c]chrysene, and benzo[g]-chrysene have been incubated with GSH in the presence of human glutathione transferases GSTM1-1 (a mu-class enzyme) and GSTP1-1 (a pi-class enzyme). As previously shown with GSTA1-1 (an alpha-class enzyme) both M1-1 and P1-1 demonstrate considerable activity toward a number of the diol epoxides studied, although a great variation in catalytic efficiency and enantioselectivity was observed. With GSTM1-1, the bay-region diol epoxides, in particular the syn-diastereomers were in most cases more efficiently conjugated with GSH than the fjord-region analogues. GSTM1-1 demonstrated an enantioselectivity ranging from no preference (50%) to high preference (> or = 90%) for conjugation of the enantiomers with R-configuration at the benzylic position of the oxirane ring. With GSTP1-1, the enzyme demonstrated appreciable activity toward both bay- and fjord-region diol epoxides and, in most cases, a preference for the anti-diastereomers. In contrast to GSTM1-1 and as previously shown for GSTA1-1, GSTP1-1 showed an exclusive preference for conjugation of the enantiomers with R-configuration at the benzylic oxirane carbon. With both GSTM1-1 and GSTP1-1, the chemically most reactive diol epoxide, the (+)-syn-enantiomer of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,-10-tetrahydrobenzo[a]pyrene (BPDE), was the best substrate. As for GSTA1-1, no obvious correlation between chemical reactivity or lipophilicity of the compounds and catalytic efficiencies was observed. Molecular modeling of diol epoxides in the active sites of GSTP1-1 and -A1-1 is in agreement with the assumption, based on functional studies, that the H-site of GSTA1-1 [Jernström et al. (1996) Carcinogenesis 17, 1491-1498] can accommodate stereoisomers of different sizes. Further, modeling of the enantiomers of anti- and syn-BPDE in the active site of GSTP1-1 provides an explanation for the exclusive preference for the enantiomers with R-configuration at the benzylic oxirane carbon. These isomers could be snuggly fitted in the H-site close to the GSH sulfur, whereas those with opposite stereochemistry could not.

Prostate cancer risk from occupational exposure to polycyclic aromatic hydrocarbons interacting with the GSTP1 Ile105Val polymorphism

“…Based on the position of the epoxide ring, PAH diol epoxides can be classified either as bay region or fjord region [43]. GSTP1 demonstrates appreciable activity toward both bay-and fjord-region diol epoxides, but shows a preference for the anti-diastereomers [44], which are more carcinogenic [45]. GSTP1 variants at codon 105 also have variable catalytic efficiencies toward PAH, which vary by the isomeric class of the molecule [46,47].…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…The catalytic efficiency of different GSTs (isoenzymes of Alpha, Mu, and Pi have been tested so far) with respect to a number of DE diastereomers and their corresponding enantiomers varies markedly. In addition, certain isoenzymes, for example, those belonging to class Pi, exhibit an exclusive preference for the DE enantiomers with R-absolute configuration at the benzylic arene carbon (of the DE isomers identified as ultimate carcinogens), whereas others (e.g., class Alpha and Mu isoenzymes) are less selective (Sundberg et al 1997).…”

Cytotoxicity and mutagenicity of dibenzo[a,l]pyrene and (±)-dibenzo[a,l]pyrene-11,12-dihydrodiol in V79MZ cells co-expressing either hCYP1A1 or hCYP1B1 together with human glutathione-S-transferase A1

“…Studies of the conjugation of the most metabolically relevant (+)-syn and (−)-anti-DBPDE metabolites indicated that the hGSTP1-1 isozyme exhibited appreciable activity toward (−)-anti and (+)-syn enantiomers of DBP diol epoxides, with preference for conjugation of the (−)-anti-diastereoisomers [20,21]. More recent studies demonstrated that purified hGSTA1-1 exhibits at least an order of magnitude more efficient activity for the conjugation of (−)-anti-DBPDE compared to hGSTM1-1 and hGSTP1-1 [22].…”

“…The (−)-anti-DBPDE stereoisomer was responsible for the majority of DBPDE-DNA adducts, and was produced as a greater proportion of the total metabolites by hCYP1B1 as compared to hCYP1A1 [17,18]. Interestingly, however, activation via hCYP1A1-mediated metabolism of DBP elicited stronger cytotoxic effects [19], possibly due to polar DNA adducts of metabolites produced only in cells expressing hCYP1A1.Studies of the conjugation of the most metabolically relevant (+)-syn and (−)-anti-DBPDE metabolites indicated that the hGSTP1-1 isozyme exhibited appreciable activity toward (−)-anti and (+)-syn enantiomers of DBP diol epoxides, with preference for conjugation of the (−)-anti-diastereoisomers [20,21]. More recent studies demonstrated that purified hGSTA1-1 exhibits at least an order of magnitude more efficient activity for the conjugation of (−)-anti-DBPDE compared to hGSTM1-1 and hGSTP1-1 [22].…”