We propose to investigate the genetic and evolutionary mechanisms which account for the existence of multiple isozymes of the microsomal mono-oxygenase, cytochrome P-450, with different but overlapping substrate specificities as well as the molecular mechanisms which operate to regulate the expression of the genes encoding these enzymes during development, in different tissues and after treatment of animals with specific inducing agents. These studies will involve a detailed structural and functional characterization of several members of a family of genes which contains the major phenobarbital-induced cytochrome P-450 of rat liver which we have already cloned as well as the isolation and similar characterization of the genes for two major constitutive cytochrome P-450 isozymes of rat liver. One of these is responsible for the testosterone 16 Alpha-hydroxylase found only in the livers of male rats and its expression in adult life is determined by """"""""androgenic imprinting"""""""" in early postnatal life of hypothalamic centers which appear to regulate the pituitary control of sex-dependent hepatic steroid metabolism. The structural studies on the P-450 genes are directed toward elucidating their interrelationships and the structural similarities of their encoded proteins. The regulatory studies deal primarily with the role of chromatin structure and DNA methylation in modulating P-450 gene expression and the identification, using DNA mediated transfection experiments with chimeric genes, of cis-acting regulatory elements involved in controlling expression of the various genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030701-05
Application #
3278506
Study Section
Molecular Biology Study Section (MBY)
Project Start
1982-02-01
Project End
1990-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012