Linked Life Data

3124956

Source:http://linkedlifedata.com/resource/pubmed/id/3124956

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1988-3-28
pubmed:abstractText
The homogeneous 3 alpha-hydroxysteroid-dihydrodiol dehydrogenase of rat liver cytosol catalyzes the NADP-dependent oxidation of a wide variety of polycyclic aromatic trans-dihydrodiols and has been implicated in their detoxification (T.E. Smithgall, R.G. Harvey, and T.M. Penning, J. Biol. Chem., 261:6184-6191,1986). This study examined the influence of methyl groups on the velocity and stereochemical course of enzymatic benz(a)anthracene (BA) trans-dihydrodiol oxidation. The racemic trans-3,4-dihydrodiols of BA and 7-methylbenz(a)anthracene (7-MBA) were completely consumed by the purified dehydrogenase, indicating that both stereoisomers are substrates. However, 50% of the ( +/- )-trans-3,4-dihydrodiols of 12-methylbenz(a)anthracene (12-MBA) and 7,12-dimethylbenz(a)-anthracene (DMBA) were oxidized, suggesting that only one stereoisomer is utilized in each case. At low substrate concentrations, enzymatic oxidation of the trans-3,4-dihydrodiols of BA, 12-MBA, and DMBA followed simple first-order kinetics. By contrast, oxidation of the 3,4-dihydrodiol of 7-MBA was of higher order, due to differences in the rate of oxidation of each stereoisomer. Rate constants estimated for each reaction indicate that the non-bay-region methyl group at position 7 has a greater enhancing effect on the rate of oxidation than the bay-region methyl group at position 12 (10- versus 4-fold, respectively). The 3,4-dihydrodiol of DMBA, which possesses both non-bay- and bay-region methyl groups, is oxidized more than 30 times faster than the unmethylated parent hydrocarbon. The absolute stereochemistry of the preferentially oxidized dihydrodiols was assigned by circular dichroism spectrometry. For the 3,4-dihydrodiols of DMBA and 12-MBA, the stereoisomer oxidized has the 3S,4S configuration. A large negative Cotton effect was observed in the circular dichroism spectrum of the 7-MBA 3,4-dihydrodiol which remained at the end of the rapid phase of oxidation of this racemic substrate, indicating that the dehydrogenase displays partial stereochemical preference for the 3S,4S enantiomer. These results suggest that methylation of BA at C-7 greatly enhances the oxidation of the 3S,4S-dihydrodiol, while the presence of a bay-region methyl group at C-12 completely blocks the oxidation of the 3R,4R-stereoisomer. Rapid, stereoselective oxidation of methylated polycyclic aromatic trans-dihydrodiols by this route in vivo may significantly influence their carcinogenicity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1227-32
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1988
pubmed:articleTitle
Oxidation of the trans-3,4-dihydrodiol metabolites of the potent carcinogen 7,12-dimethylbenz(a)anthracene and other benz(a)anthracene derivatives by 3 alpha-hydroxysteroid-dihydrodiol dehydrogenase: effects of methyl substitution on velocity and stereochemical course of trans-dihydrodiol oxidation.
pubmed:affiliation
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't