# GLUTATHIONE METABOLISM DURING SKIN TUMOR PROMOTION

> **NIH NIH R01** · KANSAS STATE UNIVERSITY · 1987 · $84,631

## Abstract

One of the earliest responses to 12-0-tetradecanoylphorbol-13-acetate (TPA)
may be the generation of reactive oxygen species.  Therefore, antioxidants
with their capacity to terminate free radical chain reactions would be
expected to modify the tumor promotion process.  Recent studies from our
laboratory indicate that TPA decreases rapidly the intracellular ratio of
reduced glutathione (GSH)/oxidized glutathione (GSSG) in epidermal cell
suspensions.  Moreover, treatments with cysteine (Cys), GSH and
Alpha-tocopherol inhibit dramatically the induction of epidermal ornithine
decarboxylase (ODC) activity by TPA, one of the essential components of
mouse skin tumor promotion, as well as the incidence of skin tumors in the
initiation-promotion protocol.  Our findings suggest that Cys and GSH might
inhibit TPA-induced ODC activity and the promotion of skin papillomas
through an increase in the intracellular ratio of GSH/GSSG.  Since the
inhibitory effects of Cys on both the decrease in the ratio of GSH/GSSG and
the induction of ODC activity by TPA are greatly reduced by the inhibitors
of Gamma-glutamyl transpeptidase (Gamma-GT) and Gamma-glutamylcysteine
synthetase, we believe it is important to rigorously study the metabolism
of GSH, a natural antioxidant which inhibits chemical carcinogenesis,
during skin tumor promotion.  First, we will study the effects of various
tumor promoters on GSH level, Gamma-GT and GSH peroxidase activities, and
O2 production in isolated epidermal cells.  Second, because functional
interrelationships between sulfur-containing amino acids, selenium, vitamin
E, and GSH peroxidase have been postulated, we will determine if treatments
including GSH level-raising agents, selenoamino acids and Alpha-tocopherol
might increase the antioxidant GSH peroxidase protective system of the
cells and inhibit the oxidative challenge linked to skin tumor promotion.
Finally, we will determine the effectiveness of combined treatments with
GSH level-raising agents, selenium-containing compounds and
Alpha-tocopherol as modifiers of the effects of TPA on GSH metabolism,
stimulators of the GSH-dependent antioxidant protective system and
inhibitors of multistage skin tumor promotion.  These studies should help
us to identify new inhibitors of skin carcinogenesis and in general should
provide a better understanding of the biochemistry of tumor promotion and
its regulation.

## Key facts

- **NIH application ID:** 3179579
- **Project number:** 5R01CA040083-03
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **SAM.gov UEI:** CFMMM5JM7HJ9
- **Principal Investigator:** Jean-Pierre H Perchellet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $84,631
- **Award type:** 5
- **Project period:** 1985-07-01 → 1988-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179579

## Citation

> US National Institutes of Health, RePORTER application 3179579, GLUTATHIONE METABOLISM DURING SKIN TUMOR PROMOTION (5R01CA040083-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179579. Licensed CC0.

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