Biomaterial Database

Prostaglandin endoperoxide synthetase-dependent cooxidation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in C3H/10T 1/2 clone 8 cells. 1982

J A Boyd, and J C Barrett, and T E Eling

(+/-)trans-7,8-Dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol), the proximate form of the carcinogen benzo(a)pyrene, is cooxidized during the oxidation of arachidonic acid to prostaglandins by prostaglandin endoperoxide synthetase (PES). This enzyme can oxidize BP-7,8-diol to the reactive intermediate (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, which binds covalently to macromolecules, is mutagenic in bacterial test systems, and forms 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP-tetrol) isomers. We have examined the cooxidation of BP-7,8-diol in an intact cell culture system of C3H/10T 1/2 clone 8 mouse embryo fibroblasts, in which both the mixed-function oxidase and PES systems are present. When BP-7,8-diol is incubated for 72 hr with approximately 10(6) confluent cells, high-performance liquid chromatography analysis of the organic extractable products reveals all four pairs of BP-tetrols, with those from (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene predominating. The addition of arachidonic acid (100 microM) produced a 2- to 3-fold increase in the formation of BP-tetrols from (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, while the metabolism of BP-tetrols from (+/-)-7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10 tetrahydrobenzo(a)pyrene was unchanged. The addition of the PES inhibitor indomethacin (100 microM) completely eliminated this stimulation. Cell transformation assays were carried out under the same conditions. The addition of arachidonic acid resulted in a 10-fold increase in foci formation, while indomethacin inhibited the increase in foci formation by 70%. These results suggest that cooxidation of BP-7,8-diol to reactive intermediates by PES can occur in an intact cell system if stimulated with arachidonic acid. In addition to mixed-function oxidase-dependent activation of carcinogens, the cooxidation of chemicals to reactive metabolites during prostaglandin biosynthesis may also play a role in carcinogenesis.

UI	MeSH Term	Description	Entries
D007213	Indomethacin	A non-steroidal anti-inflammatory agent (NSAID) that inhibits CYCLOOXYGENASE, which is necessary for the formation of PROSTAGLANDINS and other AUTACOIDS. It also inhibits the motility of POLYMORPHONUCLEAR LEUKOCYTES.	Amuno,Indocid,Indocin,Indomet 140,Indometacin,Indomethacin Hydrochloride,Metindol,Osmosin
D011451	Prostaglandin-Endoperoxide Synthases	Enzyme complexes that catalyze the formation of PROSTAGLANDINS from the appropriate unsaturated FATTY ACIDS, molecular OXYGEN, and a reduced acceptor.	Fatty Acid Cyclo-Oxygenase,PGH Synthase,Prostaglandin H Synthase,Prostaglandin Synthase,Prostaglandin-Endoperoxide Synthase,Arachidonic Acid Cyclooxygenase,Cyclo-Oxygenase,Cyclooxygenase,Cyclooxygenases,Hydroperoxide Cyclase,PGH2 Synthetase,Prostaglandin Cyclo-Oxygenase,Prostaglandin Cyclooxygenase,Prostaglandin Endoperoxide Synthetase,Prostaglandin G-H Synthase,Prostaglandin H2 Synthetase,Prostaglandin Synthetase,Cyclase, Hydroperoxide,Cyclo Oxygenase,Cyclo-Oxygenase, Fatty Acid,Cyclo-Oxygenase, Prostaglandin,Cyclooxygenase, Arachidonic Acid,Cyclooxygenase, Prostaglandin,Endoperoxide Synthetase, Prostaglandin,Fatty Acid Cyclo Oxygenase,G-H Synthase, Prostaglandin,Prostaglandin Cyclo Oxygenase,Prostaglandin Endoperoxide Synthases,Prostaglandin G H Synthase,Synthase, PGH,Synthase, Prostaglandin,Synthase, Prostaglandin G-H,Synthase, Prostaglandin H,Synthase, Prostaglandin-Endoperoxide,Synthases, Prostaglandin-Endoperoxide,Synthetase, PGH2,Synthetase, Prostaglandin,Synthetase, Prostaglandin Endoperoxide,Synthetase, Prostaglandin H2
D011453	Prostaglandins	A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes.	Prostaglandin,Prostanoid,Prostanoids
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D002471	Cell Transformation, Neoplastic	Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill.	Neoplastic Transformation, Cell,Neoplastic Cell Transformation,Transformation, Neoplastic Cell,Tumorigenic Transformation,Cell Neoplastic Transformation,Cell Neoplastic Transformations,Cell Transformations, Neoplastic,Neoplastic Cell Transformations,Neoplastic Transformations, Cell,Transformation, Cell Neoplastic,Transformation, Tumorigenic,Transformations, Cell Neoplastic,Transformations, Neoplastic Cell,Transformations, Tumorigenic,Tumorigenic Transformations
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002999	Clone Cells	A group of genetically identical cells all descended from a single common ancestral cell by mitosis in eukaryotes or by binary fission in prokaryotes. Clone cells also include populations of recombinant DNA molecules all carrying the same inserted sequence. (From King & Stansfield, Dictionary of Genetics, 4th ed)	Clones,Cell, Clone,Cells, Clone,Clone,Clone Cell
D004101	Dihydroxydihydrobenzopyrenes	Benzopyrenes saturated in any two adjacent positions and substituted with two hydroxyl groups in any position. The majority of these compounds have carcinogenic or mutagenic activity.	Benzopyrene Dihydrodiols,Dihydrobenzopyrene Diols,Dihydrodiolbenzopyrenes,Dihydrodiols, Benzopyrene,Diols, Dihydrobenzopyrene
D005347	Fibroblasts	Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.	Fibroblast
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia