# PROMOTION OF LUNG TUMORS BY BHT

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 1989 · $152,863

## Abstract

Butylated hydroxytoluene (BHT), a widely used food additive,
enhances the development in mice of lung tumors structurally
similar to bronchiolo-alveolar tumors in man.  We will investigate
the mechanisms of this stimulation of tumor multiplicity using
research tools developed during the previous grant period.  First,
evidence indicates a central role of BHT metabolism in tumor
promotion.  Metabolism in mouse lung homogenates and in lung
epithelial cells will be compared 1) in strains of mice that differ
in their sensitivity to BHT promotion, 2) in mice treated with
agents that alter the pulmonary effects of BHT, and 3) with
structurally analogous phenols that do or do not promote lung
tumors.  These results should enable us to implicate a specific
metabolic pathway or pathways in promotion.  Second, the
biochemical mechanism by which BHT causes enhanced tumor growth
will be studied by focusing on BHT-induced changes in
Ca++/phospholipid-dependent protein kinase C (Pk-C) and Ca++-
dependent protease (calpain) activities, and on the Pk-C catalyzed
phosphorylation of an endogenous lung protein substrate (p36).  The
hypothesis that subcellular translocation and subsequent activation
of both Pk-C and calpain follows BHT biotransformation will be,
tested using immunoblotting, immunocytochemistry, and partial
purification procedures.  Correlative tests to evaluate the role
of Pk-C catalyzed phosphorylation in promotion will be based on 1)
the use of strains of mice susceptible to lung tumor; induction by
urethan but resistant to tumor promotion by BHT (U+B- phenotype),
2) an analog of BHT which causes lung damage but does not promote
tumors, and 3) an agent which perturbs BHT metabolism without
affecting tumor promotion.  Third, the lung cells which actually
give rise to tumors--the alveolar type 2 cells and bronchiolar
Clara cells--will be directly examined to further elucidate the
biochemistry of tumor promotion.  Clara cells will be isolated from
U+B+ and U+B- strains of mice following, treatment with BHT-or BHT
analogs, and aspects of the p36 phosphorylation system will be
examined to genetically distinguish among biochemical mechanisms
in the cells of specific interest.  Isolated Clara cells and
established lines of both normal and neoplastic type 2 cells will
be exposed to BHT metabolites putatively involved in promotion;
effects on the p36 phosphorylating system, oxy-radical generation,
and cellular protective mechanisms will be examined.

## Key facts

- **NIH application ID:** 3171341
- **Project number:** 5R01CA033497-06
- **Recipient organization:** UNIVERSITY OF COLORADO
- **SAM.gov UEI:** SPVKK1RC2MZ3
- **Principal Investigator:** ALVIN M MALKINSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $152,863
- **Award type:** 5
- **Project period:** 1982-09-01 → 1991-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3171341

## Citation

> US National Institutes of Health, RePORTER application 3171341, PROMOTION OF LUNG TUMORS BY BHT (5R01CA033497-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3171341. Licensed CC0.

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