# LIVER CANCERS BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 1987 · $108,738

## Abstract

The proposal is aimed at clarifying the seemingly contradictory effects of
hypolipidemic peroxisome proliferators on the induction of liver tumors in
experimental animals.  While chronic administration of these agents leads
to the induction of liver tumors, their short term effects are inhibitory
or preventive to the induction of putative preneoplastic lesions.  Even
though the hypothesis that carcinogenecity of hypolipidemic peroxisome
proliferators may be mediated through excess generation of potentially
damaging oxygen radicals as a result of sustained elevation of peroxisomal
fatty acid oxidation is attractive, our preliminary study indicates that
the short term administration of these agents (BR931, DEHP) to rats does
not induce peroxidative damage to liver membrane lipids.  In this proposal,
we will evaluate whether peroxidative damage to cellular macromolecules may
be manifested after relatively long term administration of hypolipidemic
peroxisome proliferators and/or when the agents are given to aged animals.
We will determine the long term effects of these agents on microsomal and
nuclear membrane lipid peroxidation and DNA in hepatocytes damage as well
as the effects on aged rats.  Balance of selected cellular enzymes
responsible for the generation of H2O2 (palmitoyl CoA oxidation) and for
protection against peroxidative damage (catalase, superoxide dismutases,
glutathione-peroxidases, and glutathione, etc) will be evaluated to
determine time or age dependent alterations of the enzyme activities.  The
nature of prevention and regression of carcinogen-induced preneoplastic
cells to normal hepatocytes.  Finally, the possibility will be scrutinized
that the precursor lesions of liver tumors induced by hypolipidemic
peroxisome proliferators may not be the commonly accepted lesions of enzyme
altered foci.  Using various enzyme markers, H3-thymidine radioautography
and monoclonal antibodies against putative preneoplastic foci by
hypolipidemic peroxisome proliferators will be analyzed to determine
whether regression represents selective cell killing or phenotypic
reversion of preneoplastic cells, we will analyze cellular changes
associated with intermediate stages of chronic administration of these
agents.  Clarification of possible separate mechanisms (acute and chronic)
with which these agents exert their effects on the liver will provide
critical information regarding the control of genesis and progression of
cancer in general.

## Key facts

- **NIH application ID:** 3179509
- **Project number:** 5R01CA040062-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **SAM.gov UEI:** MKAGLD59JRL1
- **Principal Investigator:** HISASHI SHINOZUKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $108,738
- **Award type:** 5
- **Project period:** 1985-07-01 → 1988-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179509

## Citation

> US National Institutes of Health, RePORTER application 3179509, LIVER CANCERS BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS (5R01CA040062-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179509. Licensed CC0.

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