Dietary fat is known to enhance intestinal tumorigenesis during the promotional phase of the carcinogenic process. The actual tumor promoting agents responsible for this enhancement are unknown although suggestions include, bile acids, the caloric content of the fat, and oxidation products of polyunsaturated fatty acids. Structure-activity studies have shown the primary oxidation products of unsaturated fatty acids, in particular hydroperoxy-,hydroxy, and keto-derivatives are mitogenic to the colonic mucosa when instilled intra-rectally into animals. In that cell proliferation is an essential component of tumor promotion these findings are consistent with a role for oxidized fatty acids in the enhancement of tumorigenesis. The experiments in this proposal will investigate the colonic metabolism of 13- hydroperoxyoctadecadienoic acid (derived from linoleic acid) and related compounds in an effort to assess the production of active metabolites from the primary oxidation products of major dietary fatty acids. Metabolism of radiolabeled 13--hydroperoxyoctadecadienoic acid by colonic mucosal cell homogenates, particulate fractions, and tissue explants will be assessed. Special attention will be paid to the conversion of the hydroperoxy fatty acid to an alpha, beta- unsaturated ketone although the production of hydroxy-, epoxyhydroxy-, trihydroxy-, and other metabolites will also be evaluated. Metabolism, binding of metabolites to tissue constituents, and incorporation into lipid classes will be determined, and correlated with the stimulation of mitogenesis in the explants. The time course, dose response, and cofactor requirements for the reactions will be determined. These investigations will provide significant new information concerning the target tissue mediated metabolism of an important class of biologically active molecules, and may provide insight into the mechanism of carcinogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Oakland University
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Bronstein, J C; Bull, A W (1997) Substrate specificity and characterization of partially purified rat liver 13-hydroxyoctadecadienoic acid (13-HODE) dehydrogenase. Arch Biochem Biophys 348:219-25
Bull, A W; Bronstein, J C; Earles, S M et al. (1996) Formation of adducts between 13-oxooctadecadienoic acid (13-OXO) and protein-derived thiols, in vivo and in vitro. Life Sci 58:2355-65
Bronstein, J C; Bull, A W (1993) The correlation between 13-hydroxyoctadecadienoate dehydrogenase (13-HODE dehydrogenase) and intestinal cell differentiation. Prostaglandins 46:387-95
Bull, A W; Earles, S M; Blackburn, M L (1993) Regulation of the induction of ornithine decarboxylase in short-term rat colon organ culture by dexamethasone and 13-hydroxyoctadecadienoic acid (13-HODE). Life Sci 53:377-85
Brar, R S; Bull, A W (1993) Effect of alkyl sulfides on diazomethane-induced methylation of DNA in vitro. Cancer Lett 73:121-5
Desai, T K; Parikh, N; Bronstein, J C et al. (1992) Failure of rectal ornithine decarboxylase to identify adenomatous polyp status. Gastroenterology 103:1562-7
Earles, S M; Bronstein, J C; Winner, D L et al. (1991) Metabolism of oxidized linoleic acid: characterization of 13-hydroxyoctadecadienoic acid dehydrogenase activity from rat colonic tissue. Biochim Biophys Acta 1081:174-80
Bull, A W; Earles, S M; Bronstein, J C (1991) Metabolism of oxidized linoleic acid: distribution of activity for the enzymatic oxidation of 13-hydroxyoctadecadienoic acid to 13-oxooctadecadienoic acid in rat tissues. Prostaglandins 41:43-50
Bull, A W; Bronstein, J C (1990) Production of unsaturated carbonyl compounds during metabolism of hydroperoxy fatty acids by colonic homogenates. Carcinogenesis 11:1699-704