title: Detoxification of optically active bay- and fjord-region polycyclic aromatic hydrocarbon dihydrodiol epoxides by human glutathione transferase P1-1 expressed in Chinese hamster V79 cells.
abstract: Dihydrodiol epoxides (DEs) are important carcinogenic metabolites of polycyclic aromatic hydrocarbons (PAHs). The metabolic formation of four stereoisomeric DEs (a pair of optically active diastereomers termed as syn- and anti-form) is possible. Glutathione tranferases (GSTs) have been demonstrated to catalyze the detoxification of DEs. Purified GSTs display remarkable differences in catalytic efficiencies towards bay- and fjord-region DEs along with a high degree of regio- and stereoselectivity. Here we determined to which extent heterologously expressed human GSTP1-1, a major GST isoform in lung, affects the mutagenicity of stereoisomeric bay-region DEs of benzo[a]pyrene in Chinese hamster V79 cells. To evaluate the influence of sterical crowding in the substrate on the activity of GSTP-1, the study was extended to the strongly mutagenic fjord-region (-)-anti-DEs of benzo[c]phenanthrene and dibenzo[a,l]pyrene. GSTP1-1,reduced preferentially the mutagenicity (studied at the hprt locus) of (+)-anti and (+)-syn-DEs of benzo[a]pyrene (by 66 and 67%) as compared with the corresponding (-)-anti- and (-)-syn-enantiomers (by 15 and 13%). These results are in line with previous studies on the enantioselectivity of purified GSTP1-1 towards the DE isomers of benzo[a]pyrene and benzo[c]phenanthrene showing that enantiomers with (R)-configuration at the benzylic oxiranyl carbon are better substrates than those with (S)-configuration. Interestingly, the (-)-anti-DEs of benzo[c]phenanthrene and dibenzo[a,l]pyrene were efficiently detoxified by GSTP-1-1 in the constructed cell line (reduction of mutagenicity by 66 and 64%). This study demonstrates that differences in the caalytic activity seen for purified GST towards individual mutagens do not necessarily reflect the detoxification of DEs by the same enzyme in a living cell and provides further evidence that specific human GSTs play a role in the detoxification of DEs of PAHs.
authors.affiliation: Institute of Toxicology, University of Mainz, Germany. aseidel@goofy.zdv.uni-mainz.de
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: T
authors.initials: T
authors.lastname: Friedberg
authors.forename: B
authors.initials: B
authors.lastname: Löllmann
authors.forename: A
authors.initials: A
authors.lastname: Schwierzok
authors.forename: M
authors.initials: M
authors.lastname: Funk
authors.forename: H
authors.initials: H
authors.lastname: Frank
authors.forename: R
authors.initials: R
authors.lastname: Holler
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.forename: H
authors.initials: H
authors.lastname: Glatt
mesh_terms: D000818:Animals; D018383:Bay-Region, Polycyclic Aromatic Hydrocarbon; D002273:Carcinogens / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004852:Epoxy Compounds / Q000378:metabolism*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D002273:Carcinogens; D004852:Epoxy Compounds; D007527:Isoenzymes; D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase