# SUICIDE INHIBITORS OF CYTOCHROME P450 AS ANTICARCINOGENS

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 1993 · $92,162

## Abstract

The long-range objective of our research program is to develop
mechanism based irreversible inactivators (suicide inhibitors) that
will be selective for particular P450 isozymes and that can therefore
be used to investigate the mechanism of chemical carcinogenesis.  The
three broad objectives of this proposed research are subdivided into
a set of specific aims.

I.    The synthesis and investigation of ethynyl compounds as suicide
inhibitors of P450 isozymes potentially involved in chemical
precarcinogen activation in humans.  1. 2-Ethynyl and 4-ethynylpyrene
(2EP, 4EP) will be tested as suicide inhibitors of P4501A1.  2. Ethynyl
derivatives of adamantane will be tested as suicide inhibitors capable
of differentiating P4501A2, 2B1, and 2E1 dependent activities.  3. 4-
Ethynylacetanilide will be investigated as a potential selective
suicide inhibitor of P4501A2 from human liver.

II.   The effects of ethynyl suicide inhibitors of P450 isozymes will
be examined in model biological systems selected to demonstrate the
potential use of such reagents in studies of chemical carcinogenesis.
1. 2EP and 4EP will be tested as selective in vivo inhibitors of
benzo[a]pyrene and of 7,12-dimethylbenz[a]anthracene (DMBA) induced
skin tumors in the two-stage mouse model 2.  Experiments will be
carried out to establish why co-application of 2-ethynylnaphthalene
(2EN) changes the mutational spectrum produced by DMBA in mouse skin
and causes both H-ras and K-ras mutations in the resulting tumors.  3.
The effects of selective ethynyl inhibitors of P450 isozymes upon the
metabolism of the tobacco specific nitrosamine, 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanone in bronochiolar Clara cells and aveolar type
II cells from mouse lung will be determined.

III.  Selective ethynyl inhibitors will be used as active site probes
to label and identify features of the substrate binding sites of P450
isozymes.  1. Samples of (3)H-labeled ethynyl compounds will be used
to label the active site regions of P4501A1, 1A2, 2B1, and 2E1 and the
sites of the labeling established by proteolysis of the labeled P450
proteins and separation and identification of the resulting labeled
peptides.  2. Fluorine-labeled 2EN will be used to label the active
site region of P4502B1 and fluorine-NMR then used to establish the
relative orientation of the fluorine label on the bound ethynyl
inhibitor to the P450 heme iron.

Appropriately designed ethynyl compounds, because of their special
biological activities, can be used to make significant contributions
to investigations of fundamental aspects of P450 involvement in
chemical carcinogenesis.

## Key facts

- **NIH application ID:** 3176271
- **Project number:** 2R01CA038192-04A2
- **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:** 1993
- **Award amount:** $92,162
- **Award type:** 2
- **Project period:** 1987-02-01 → 1996-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176271

## Citation

> US National Institutes of Health, RePORTER application 3176271, SUICIDE INHIBITORS OF CYTOCHROME P450 AS ANTICARCINOGENS (2R01CA038192-04A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176271. Licensed CC0.

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