Carcinogenesis, Vol 19, 1975-1981, Copyright © 1998 by Oxford University Press
A Seidel, T Friedberg, B Lollmann, A Schwierzok, M Funk, H Frank, R Holler, F Oesch and H Glatt
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.
ARTICLES
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
Institute of Toxicology, University of Mainz, Germany. aseidel@goofy.zdv.uni-mainz.de
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