# DIHYDRODIOL DEHYDROGENASE AND PAH METABOLISM

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 1992 · $149,195

## Abstract

This application will continue with a systematic study of the role of
dihydrodiol dehydrogenase in the detoxification of proximate and ultimate
carcinogens of polycyclic aromatic hydrocarbons (PAH). The research
program includes, chemical, biochemical, cellular and human studies
designed to provide information on the role of this enzyme in PAH
metabolism.

We have shown that the homogeneous dihydrodiol dehydrogenase from rat
liver cytosol oxidizes a wide variety of non-K-region trans-dihydrodiols
of carcinogenic PAH to the corresponding ortho-quinones which can be
trapped as mercaptoethanol adducts.  To characterize this alternative
pathway of proximate carcinogen metabolism, the reactivity of non-K-
region ortho-quinone products towards cellular nucelophiles (e.g.,
cysteine and glutathione) will be examined, the influence of bay-region
methylation on reactivity will be determined, and structures of
glutathione adducts will be elucidated.  To determine whether glutathione
conjugation is enzyme catalyzed, the ability of the ortho-quinone
products to act as substrates for six glutathione-S-transferases purified
from rat liver cytosol will be assessed.

The involvement of dihydrodiol dehydrogenase in ultimate carcinogen
metabolism will be examined by testing (+)-anti-diol-epoxides of
naphthalene, phenanthrene, chrysene, 5-methylchrysene and benzo[a]pyrene
as substrates.

Rat hepatoma cells (H-4IIe) known to contain dihydrodiol dehydrogenase
will be incubated with the 7,8-trans-dihydrodiol of benzo[a]pyrene and if
possible the glutathione adduct of the 7,8-ortho-quinone of
benzo[a]pyrene will be identified as a cellular metabolite.  The
metabolism of the 7,8-trans-dihydrodiol of benzo[a]pyrene will be studied
in H-4IIe cells in the presence of known inhibitors of dihydrodiol
dehydrogenase [e.g., indomethacin, 6-medroxyprogesterone acetate and the
suicide substrate 1-(4'-nitrophenyl)-2-propen-1-o1].  If the
dehydrogenase plays a significant role in PAH metabolism enzyme
inhibition should result is an increase in diol-epoxides of
benzo[a]pyrene (detected as tetraols and DNA adducts).  Human liver
hepatoma (Hep-G2) and hamster embryo cells will also be screened for the
drug sensitive dihydrodiol dehydrogenase.  If present the experiments
described for H-4IIe cells will be repeated.

To determine whether dihydrodiol dehydrogenase plays a role in PAH
metabolism in humans, the enzyme will be detected in human liver samples
by enzyme assay and Western blot analysis.  Activities will be resolved
by chromatography and isozymes which oxidize the 7,8-trans-dihydrodiol of
benzo[a]pyrene will be identified.  The mRNA species coding for the human
enzyme will be identified by Northern analysis using the cDNA for the rat
liver enzyme.

## Key facts

- **NIH application ID:** 3178566
- **Project number:** 5R01CA039504-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **SAM.gov UEI:** GM1XX56LEP58
- **Principal Investigator:** Trevor M Penning
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $149,195
- **Award type:** 5
- **Project period:** 1986-03-01 → 1993-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178566

## Citation

> US National Institutes of Health, RePORTER application 3178566, DIHYDRODIOL DEHYDROGENASE AND PAH METABOLISM (5R01CA039504-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178566. Licensed CC0.

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