Document Detail

Prostaglandin endoperoxide synthetase-dependent cooxidation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in C3H/10T 1/2 clone 8 cells.
MedLine Citation:
PMID:  6805944     Owner:  NLM     Status:  MEDLINE    
(+/-)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.
J A Boyd; J C Barrett; T E Eling
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer research     Volume:  42     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1982 Jul 
Date Detail:
Created Date:  1982-08-14     Completed Date:  1982-08-14     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2628-32     Citation Subset:  IM    
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MeSH Terms
Arachidonic Acid
Arachidonic Acids / pharmacology
Benzopyrenes / metabolism*,  pharmacology
Cell Line
Cell Transformation, Neoplastic / chemically induced
Cells, Cultured
Clone Cells / metabolism
Fibroblasts / metabolism
Indomethacin / pharmacology
Prostaglandin-Endoperoxide Synthases / metabolism*
Prostaglandins / biosynthesis
Reg. No./Substance:
0/Arachidonic Acids; 0/Benzopyrenes; 0/Dihydroxydihydrobenzopyrenes; 0/Prostaglandins; 13345-25-0/benzo(a)pyrene 7,8-dihydrodiol; 506-32-1/Arachidonic Acid; 53-86-1/Indomethacin; EC Synthases

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