Abstract

The enzyme complex prostaglandin endoperoxide synthetase (PES) catalyzes the oxygenation of arachidonic acid (20:4) to the hydroperoxy endoperoxide PGG2 and the reduction of PGG2 to the hydroxy endoperoxide PGH2. During the reduction of PGG2 to PGH2, oxidizing agents are released which trigger the cooxygenation of a variety of xenobiotics. Among these are polycyclic aromatic hydrocarbons such as benzo(a)pyrene (BP) and 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol). BP-7,8-diol is cooxygenated to a diolepoxide which is believed to be the ultimate carcinogenic form of BP. We are investigating the mechanism of BP-7,8-diol cooxygenation, its occurrence in various tissues of mice and rats, and the enzymes involved. These studies will help to define the role of PES in xenobiotic metabolism and the extent to which it occurs in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM023642-09
Application #
3271809
Study Section
Biochemistry Study Section (BIO)
Project Start
1977-01-01
Project End
1986-12-31
Budget Start
1985-01-01
Budget End
1986-12-31
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Wayne State University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Marnett, L J (1990) Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as reactive intermediates. Environ Health Perspect 88:5-12
Odenwaller, R; Chen, Y N; Marnett, L J (1990) Preparation and proteolytic cleavage of apoprostaglandin endoperoxide synthase. Methods Enzymol 187:479-85
Chen, Y N; Marnett, L J (1989) Heme prosthetic group required for acetylation of prostaglandin H synthase by aspirin. FASEB J 3:2294-7
Ple, P; Marnett, L J (1989) Alkylaryl sulfides as peroxidase reducing substrates for prostaglandin H synthase. Probes for the reactivity and environment of the ferryl-oxo complex. J Biol Chem 264:13983-93
Marnett, L J; Chen, Y N; Maddipati, K R et al. (1989) Localization of the peroxidase active site of PGH synthase. Adv Prostaglandin Thromboxane Leukot Res 19:458-61
Marnett, L J; Chen, Y N; Maddipati, K R et al. (1988) Functional differentiation of cyclooxygenase and peroxidase activities of prostaglandin synthase by trypsin treatment. Possible location of a prosthetic heme binding site. J Biol Chem 263:16532-5
Chen, Y N; Bienkowski, M J; Marnett, L J (1987) Controlled tryptic digestion of prostaglandin H synthase. Characterization of protein fragments and enhanced rate of proteolysis of oxidatively inactivated enzyme. J Biol Chem 262:16892-9
Marnett, L J (1987) Peroxyl free radicals: potential mediators of tumor initiation and promotion. Carcinogenesis 8:1365-73
Lambeir, A M; Markey, C M; Dunford, H B et al. (1987) Spectral properties of the higher oxidation states of prostaglandin H synthase. Adv Prostaglandin Thromboxane Leukot Res 17A:25-8
Markey, C M; Alward, A; Weller, P E et al. (1987) Quantitative studies of hydroperoxide reduction by prostaglandin H synthase. Reducing substrate specificity and the relationship of peroxidase to cyclooxygenase activities. J Biol Chem 262:6266-79

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