# MECHANISM OF CARCINOGENESIS OF POLYCYCLIC HYDROCARBONS

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 1989 · $172,563

## Abstract

The objective is to elucidate the mechanisms of carcinogenesis of the major
classes of polycyclic aromatic hydrocarbons (PAH) at the molecular level.

It is proposed to extend our investigations of the role of substituent
effects in the metabolic activation and DNA binding of carcinogenic PAH to
obtain evidence for the hypothesis that the apparently unique importance of
the bay region in carcinogenicity is not soley the exceptional chemical
reactivity of the carbocation intermediates generated in this region, but
also the steric inhibition of enzymatic detoxification conferred by this
crowded molecular region which allows these epoxide intermediates to
survive sufficiently long in vivo to alkylate DNA.  The findings will be
utilized to relate molecular structural factors, steric and electronic, to
activation or deactivation of PAH carcinogens and predict the nature of the
active metabolites formed for a wide range of substituted and unsubstituted
PAH.

Specifically, it is proposed to synthesize the active carcinogenic
metabolites of a series of PAH for which the active forms are predicted to
be sterically hindered arene oxides, diol epoxides, or triol epoxides
(dependent upon molecular structural differences).  These compounds will be
utilized subsequently in studies of PAH metabolism, DNA binding,
mutagenicity, and carcinogenicity.  The findings will provide evidence for
the hypothesis that there are multiple types of active carcinogenic
metabolites of PAH, and an essential requirement for the activity in
addition to electrophilic reactivity is relative resistance to the action
of epoxide hydrase, glutathione-S-transferase, and other detoxifying
enzymes.  These compounds will also be furnished to other investigators who
request them for pertinent biological studies.

The findings will provide the information essential to formulation of a
comprehensive theory of PAH carcinogenesis.  This will make possible
accurate prediction of carcinogenic activity of the wide range of PAH
compounds which are ubiquitous in the human environment.

## Key facts

- **NIH application ID:** 3173591
- **Project number:** 5R01CA036097-06
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **SAM.gov UEI:** ZUE9HKT2CLC9
- **Principal Investigator:** RONALD G HARVEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $172,563
- **Award type:** 5
- **Project period:** 1984-03-01 → 1992-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173591

## Citation

> US National Institutes of Health, RePORTER application 3173591, MECHANISM OF CARCINOGENESIS OF POLYCYCLIC HYDROCARBONS (5R01CA036097-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173591. Licensed CC0.

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