# SUICIDE SUBSTRATES OF CYTOCHROME P-450 AS ANTICARCINOGEN

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 1989 · $119,170

## Abstract

Ethynylpyrene functions as a selective suicide substrate of the cytochrome
P-450c dependent benzo[a]pyrene hydroxylase activity in rat liver
microsomes.  Ethynylpyrene can also decrease mammalian cell-mediated
mutagenesis by 7,12-dimethylbenz[2]anthracene.  Ethynylpyrene may therefore
be a representative of a class of compounds which could be used to block
the P-450 dependent conversions of polycyclic arylhydrocarbons into their
mutagenic and carcinogenic derivatives.

Reconstituted monooxygenase systems containing purified cytochrome P-450b
or P-450c will be used to study the mechanism responsible for the
inhibitory action of ethynylpyrene upon benzo[a]pyrene hydroxylase.  The
products of the P-450 dependent metabolism of ethynylpyrene will be
determine, the partition ratio for product release and enzyme inactivation
established, the presence of an ethynylpyrene derivative covalently
attached to the P-450 proteins investigated, and a potential mechanism of
the inhibition tested.  A series of compounds related to ethynylpyrene will
be synthesized and structure-activity relationships determined.  The
effects of modifying both the aryl nucleus and the potential "suicide
substituent" of these structures upon P-450 dependent activities will be
established.  The effects of the different structural features upon the
selectivity of the potential suicide substrates for the benzo[a]pyrene
hydroxylase, benzphetamine demethylase, ethylmorphine demethylase,
ethoxyresofurin deethylase, and 17-Beta-estradiol 2-hydroxylase activities
of microsomes, as well as the effects of these different features upon
P-450 destruction will be determined.  The effects of selective suicide
substrates upon the distribution of metabolites produced from R- and
S-warfarin and from 2-acetylaminofluorene by rat liver microsomes, and from
benzo[a]pyrene by human epidermal keratinocytes, will be analyzed.  The
series of compounds related to ethynylpyrene will also be tested as
inhibitors of the cell-mediated mutagenesis due to
7,12-dimethylbenz[a]anthracene metabolism.  A suicide inhibitor of P-450c
will also be tested in vivo as an inhibitor of arylhydrocarbon
tumorigenesis in mice.

The results of this proposed research could lead ultimately to the design
of selective suicide substrates for the P-450 dependent monooxygenases.
Such inhibitors could be used to selectively inactivate the P-450 dependent
isozymes involved converting procarcinogens such as benzo[a]pyrene into
their carcinogenic metabolites.

## Key facts

- **NIH application ID:** 3176273
- **Project number:** 5R01CA038192-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **SAM.gov UEI:** XNY5ULPU8EN6
- **Principal Investigator:** WILLIAM L ALWORTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $119,170
- **Award type:** 5
- **Project period:** 1987-02-01 → 1990-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176273

## Citation

> US National Institutes of Health, RePORTER application 3176273, SUICIDE SUBSTRATES OF CYTOCHROME P-450 AS ANTICARCINOGEN (5R01CA038192-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176273. Licensed CC0.

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