Carcinogenesis, Vol 19, 639-648, Copyright © 1998 by Oxford University Press
A Luch, KL Platt and A Seidel
Metabolic activation of the racemic benzo[c]chrysene-trans-9,10-,
benzo[g]chrysene-trans-11,12- and dibenzo[a,l]pyrene-trans-11,12-
dihydrodiols to fjord region syn- and anti-dihydrodiol epoxides by
microsomes of Aroclor 1254-treated Sprague-Dawley rats has been examined.
Since the fjord region dihydrodiol epoxides were hydrolytically unstable
under the experimental conditions, their enzymatic formation was determined
by analyzing the tetraols as their products of acidic hydrolysis upon
addition of perchloric acid. The various stereoisomeric tetraols formed
were separated by HPLC and identified by co-chromatography with authentic
tetraols, which had been prepared by acidic hydrolysis of synthetically
available syn- and anti- dihydrodiol epoxides and characterized by NMR and
UV spectroscopy. Under standardized conditions the acidic hydrolysis of
syn-dihydrodiol epoxides of benzo[c]chrysene, benzo[g]chrysene and
dibenzo[a,l]pyrene resulted in the formation of two tetraols with cis/trans
ratios of 81:19, 77:23 and 80:20, respectively, whereas the
anti-dihydrodiol epoxides underwent almost exclusively trans hydrolysis.
The proportion of the stereoisomeric tetraols obtained from microsomal
incubations indicates that all three dihydrodiols are predominantly
oxidized at the adjacent olefinic double bond to the anti-diastereomers of
the corresponding fjord region dihydrodiol epoxides accounting for 4-35% of
the ethyl acetate-extractable metabolites. To allow quantitative assessment
of the metabolites 3H-labeled trans-dihydrodiols were synthesized by
reduction of the corresponding o-quinones with sodium borotritide.
Metabolic conversion of benzo[c]chrysene-trans-9,10- and
dibenzo[a,l]pyrene-trans-11,12-dihydrodiol by rat liver microsomes were in
a similar low range during the first 10 min of incubation (6.2 +/- 1.2 and
3.4 +/- 1.0 nmol substrate/nmol cytochrome P450/10 min, respectively),
whereas the conversion of benzo[g]chrysene-trans-11,12- dihydrodiol was
much higher (20.6 +/- 2.2 nmol substrate/nmol cytochrome P450/10 min).
Given the strong intrinsic mutagenic and carcinogenic activity of the fjord
region dihydrodiol epoxides, our data indicate that their formation, even
at a relatively low level, may contribute significantly to the biological
activity of the parent hydrocarbons.
ARTICLES
Synthesis of fjord region tetraols and their use in hepatic biotransformation studies of dihydrodiols of benzo[c]chrysene, benzo[g]chrysene and dibenzo[a,l]pyrene
Institute of Toxicology, University of Mainz, Germany.
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