Epidemiologic studies have provided evidence that a major fraction of human cancer is due to environmental factors. In line with this contention a chemical etiology of prostatic cancer has been suggested. Most mutagens and carcinogens undergo enzymatic activation to electrophiles which bind covalently to proteins, RNA and DNA. The participating enzymes, e.g. cytochrome P-450, are normally active in the metabolism of endogenous compounds such as steroid hormones. Knowledge about uptake and metabolism of mutagens and carcinogens in a particular target tissue such as the prostate not only requires insights into the function of participating enzymes, but also necessitates information about macromolecules in the tissue that bind the xenobiotic and thereby may cause a selective accumulation and/or transport of the compound in the target cells. We propose to purify, characterize and attempt to determine the toxicological significance of macromolecules in the rat and human prostate gland which interact with xenobiotics, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons (PAH), and metabolites of polychlorinated biphenyls (PCB). These binding species include, respectively, the so-called TCDD receptor, which is thought to play a role in the mechanism of induction of a certain isozyme of cytochrome P-450, Prostatic Secretion Protein (PSP), which binds TCDD and PAH's and may selectively concentrate these xenobiotics in the gland, and a macromolecule which binds methyl sulphones of PCB's. We also propose to characterize both inducible and constitutive isozymes of cytochrome P-450 in the rat and human prostate. The enzymes will be purified, antibodies will be raised against them and their respective cDNA's will be cloned. The molecular mechanisms underlying the specific expression of certain isozymes of cytochrome P-450 and lack of expression of other P-450 isozymes in the prostate will be investigated at the genomic level. Knowledge about mechanisms involved in binding, transport and metabolism of mutagens/carcinogens in the prostate should provide a better understanding of the role and nature of chemical prostatic carcinogenesis in the etiology of prostatic carcinoma.
| Soderkvist, P; Poellinger, L; Toftgard, R et al. (1988) Differential expression of the cytochrome P-450c and P-450d genes in the rat ventral prostate and liver. Cancer Res 48:3045-9 |
| Sundin, M; Warner, M; Haaparanta, T et al. (1987) Isolation and catalytic activity of cytochrome P-450 from ventral prostate of control rats. J Biol Chem 262:12293-7 |
| Soderkvist, P; Poellinger, L (1987) Involvement of the prostatic steroid-binding protein in the transfer of ligand to the dioxin receptor. Carcinogenesis 8:1287-90 |
