# DIHYDRODIOL DEHYDROGENASE AND THE ASPIRIN-LIKE DRUGS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 1987 · $111,897

## Abstract

Indirect evidence suggests that dihydrodiol dehydrogenase (EC 1.3.1.20)
prevents the formation of the diol-epoxides of polycyclic aromatic
hydrocarbons (ultimate carcinogens) by oxidizing their trans-dihydrodiol
precursors to the noncarcinogenic catechols.  We have purified the
dihydrodiol dehydrogenase from rat liver cytosol and have found it to be
potently inhibited by the nonsteroidal anti-inflammatory drugs (NSAIDS)
i.e. by the same low concentrations that would inhibit cyclooxygenase.
This proposal will determine whether this enzyme plays a crucial role in
the detoxification of chemical carcinogens and will investigate whether its
inhibition by the "aspirin-like" drugs represents a mechanism by which the
initiation of tumor formation is enhanced.  We will determine whether the
dehyrogenase preferentially oxidizes proximate carcinogens, i.e. the non-K
region trans-dihydrodiols of phenanthrene, chrysene, 5-methyl chrysene and
benzo[a]pyrene.  Racemic (plus-minus) trans-dihydrodiol substrates will be
used in these studies and the stereochemical course of the reaction will be
elucidated by measuring the CD spectra of the unreacted enantiomers.  The
products of these dehyrogenation reactions will be vigorously identified as
the corresponding catechols by trapping them as their diacetates.  The
ability of the NSAIDS to enhance chemical carcinogenesis will be examined.
Thus we will test these drugs as inhibitors of the enzyme catalyzed
detoxification reactions described.  Using the Ames Test as an end point
for diol-epoxide formation we will show that the purified enzyme reduces
the mutagenicity of benzo[a]pyrene and that this effect can be reversed by
micromolar concentrations of indomethacin.  In related studies we will
measure the levels of dihydrodiol dehydrogenase in sites of polycyclic
aromatic hydrocarbon induced chemical carcinogenesis, e.g. the lung, testis
and mammary gland of Sprague-Dawley rats and the lung, kidney and
forestomach of C3H mice.  We will determine whether the oxidation of
trans-dihydrodiols in these tumor sensitive tissues is inhibited by the
"aspirin-like" drugs.  As a prelude to demonstrating that the
co-administration of benzo[a]pyrene and indomethacin results in the
enhanced initiation of skin tumors, skin of mice strains used in
tumorgenicity studies will be screened for the presence of the indomethacin
sensitive enzyme.

## Key facts

- **NIH application ID:** 3178562
- **Project number:** 5R01CA039504-02
- **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:** 1987
- **Award amount:** $111,897
- **Award type:** 5
- **Project period:** 1986-03-01 → 1989-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178562

## Citation

> US National Institutes of Health, RePORTER application 3178562, DIHYDRODIOL DEHYDROGENASE AND THE ASPIRIN-LIKE DRUGS (5R01CA039504-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178562. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*