Cytochrame P-450 containing monooxygenase enzyme system metabolizes drugs, chemical carcinogens, xenobiotics and endogenous substrates in animals and man. Hamster is particularly prone to tumorigenesis, chemical carcinogenesis and metabolic disorders and consequently is an excellent animal model for study of human liver diseases. In this research proposal, we will study the induction and regulation of multiple forms of cytochrome P-450 in hamster liver and lung by drugs and carcinogens. We will isolate the major forms of cytochromes P-450 and study the enzyme level by immunotitration, reconstitution, and in vitro translation of mRNA's coding for these cytochrome P-450's. The mutiplicity of pulmonary cytochrome P-450 also will be studied in comparison with hepatic enzymes. We will also identify and purify the form(s) of cytochrome P-450 which metabolize the 7 Alpha hydroxylation of cholesterol from hamsters treated with cholestyramine. In addition, cholesterol gallstones will be produced in hamsters by feeding animals with estrogen and cholesterol. We will study the regulation of cholesterol 7 Alpha-hydroxylase activity and establish any link between this enzyme activity and cholesterol gallstone formation. Our objective of this research is to use the hamster as an animal model to understand the induction of cytochrome P-450 by drugs and carcinogens, the mechanism of activation of chemical carcinogens, and the molecular mechanism of gallstone disease.
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