EFFECT OF ENZYME INDUCERS ON LIVER PRENEOPLASTIC LESIONS

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Chemical carcinogenesis is a multi-step process which can be influenced by variety of exogenous and endogenous factors. Most studies examining the effects of environmental and dietary substances on the carcinogenic process have focused on changes in the first step - initiation. However, there is increasing evidence that dietary and environmental chemicals which are effective biotransformation enzyme inducers may also modify later stages of the carcinogenic process. It appears that many non-genotoxic carcinogens may act in this manner. Compared to our understanding of the role of enzyme induction in the initiation step of carcinogenesis, relatively little is known about the relationship between enzyme induction and post-initiation events such as tumor promotion and progression. It has been recognized for many years that the same enzyme system responsible for biotransformation of xenobiotics also metabolize endogenous substances, especially steroid hormones. It is also known that the intracellular concentration of a variety of endogenous hormones can substantially alter cell growth and differentiation, processes intimately involved in tumor promotion and progression. The long range objective of this study is to understand how environmental and dietary factors influence the development and progression of chemical carcinogenesis, especially "post-initiation" events such as tumor promotion and progression. The primary goal of this grant is to investigate whether there is a causal connection between the tumor promoting abilities of non-genotoxic "environmental" carcinogens and their ability to induce, or not induce, specific isoenzymes of cytochrome P-450 in different preneoplastic lesions and normal tissue. We intend to use two "short-term" altered foci / nodule models which vary in their responsiveness to induction of cytochromes P450: the widely used "Solt-Farber" model which uses DEN and AAF to induce foci and nodules (SF-HHNs), and an altered foci and nodule model produce with aflatoxin Bl. The specific aims of this study are to: I.Evaluate the mechanism(s) by which Solt-Farber nodules are stimulated to expand by short-term treatment with phenobarbital; 2. Determine whether other PBtype inducers such as 2,2',4,4'-tetrachlorobiphenyl and DDT, or 3-MC-type inducers such as 3,3',4,4'tetrachlorobiphenyl and TCDD, produce a similar dramatic expansion of SF-HHNs, and whether an inducer only acts on specific foci/nodule populations which have an altered "induction responsiveness" of specific P450s. 3. Determine: a) whether phenobarbital expansion of SF-HHN requires the presence normal levels of thyroid or sex hormones; b) whether SF-HHNs have more bound forms of hormones and/or their respective receptors; c) whether microsomal hydroxylation activities toward testosterone or estradiol, and deiodination and/or glucuronide conjugation activities toward T3 are lower in SF-HHNs than the surrounding tissue; 4. Determine the profile of alterations in specific cytochromes P-450 in SF-HHN, using immunohistology and in situ hybridization with specific antibodies and specific oligonucleotide probes.