Journal Article

Carcinogen substrate specificity of human COX-1 and COX-2

Frederick W. Wiese, Patricia A. Thompson and Fred F. Kadlubar

in Carcinogenesis

Volume 22, issue 1, pages 5-10
Published in print January 2001 | ISSN: 0143-3334
Published online January 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.1.5
Carcinogen substrate specificity of human COX-1 and COX-2

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The activation of carcinogenic aromatic and heterocyclic amines and benzo[a]pyrene-7,8-diol to intracellular electrophiles by prostaglandin H synthase (COX) is well documentedfor ovine sources of this enzyme. Here, the arachidonic acid-dependent activation of substrates by human (h)COX-1 and-2 is examined, utilizing recombinant enzymes. The COX-dependent activation of benzidine (BZ), 4-aminobiphenyl, (+)benzo[a]pyrene-7,8-diol, (+)benzo[a]pyrene-7,8-diol, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), and 4,4′-methylenebis(2-chloroaniline) (MOCA) is assessed by means of COX-catalyzed, covalent DNA binding. The hCOX isozymes activated all substrates tested, activation varied from barely detectable for IQ (0.76 and 1.52 pmol bound/mg DNA for COX-1 and -2, respectively) to a high of 65 and 117 pmol bound/mg DNA for COX-1 and -2, respectively, for the activation of MOCA. BZ, which is an excellent peroxidase substrate, did not exhibit high DNA binding levels in hCOX assays and this phenomenon was found to be due to high levels of binding to protein, which effectively competed with the DNA for binding in the assay. The demonstrated ability of the COX enzymes to activate a variety of environmental and dietary carcinogens indicates a potential role for COX in the activation pathway of aromatic and heterocyclic amines and polycyclic hydrocarbons at extra-hepatic sites during early or late stages of carcinogenesis.

Keywords: ABP, 4-aminobiphenyl; BP, benzo[a]pyrene; BSA, bovine serum albumin; BZ, benzidine; CHO, Chinese hamster ovary; COX or PGHS, prostaglandin H synthase; hCOX, human COX; IQ, 2-amino-1-methylimidazo[4,5-f]quinoline; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline; MOCA, 4,4'-methylenebis(2-chloroaniline); oCOX, ovine COX; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine.

Journal Article.  4847 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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