Xenobiotic Metabolism by Prostaglandin Endoperoxide Synthetase

Eling, Thomas E.; Boyd, J.; Reed, Gregory A.; Mason, Ronald P.; Sivarajah, Kandiah

doi:10.3109/03602538308991420

Cited by 81 publications

(18 citation statements)

References 72 publications

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“…It is likely that CYP2S1 reacts with lipid hydroperoxides, as do many P450 enzymes, through a shunt reaction that generates lipid alkoxy and peroxy radicals (Dix et al, 1985;Rota et al, 1997). These radicals, in turn, can enter into cooxidation reactions outside of the confines of the enzyme active site (Eling et al, 1983). The oxidation of polycyclic aromatic hydrocarbons observed under such conditions is therefore unlikely to be any more physiologically significant for CYP2S1 than for other P450 enzymes.…”

Section: Discussionmentioning

confidence: 99%

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Nishida

Lee²,

Montellano³

2010

Molecular Pharmacology

104

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AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.

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Section: Discussionmentioning

confidence: 99%

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Nishida

Lee²,

Montellano³

2010

Molecular Pharmacology

104

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“…One explanation for the failure of previous workers to show tetrahydrotetrol formation is that it may only form through cooxygenation ofthe dihydrodiol by cyclooxygenase (35,36). When we added arachidonic acid (0.1 IAM), it had no effect on formation of the tetrahydrotetrol, dihydrodiol, the phenols, or the 3,6-and 6,12-diones (data not shown).…”

Section: Resultsmentioning

confidence: 64%

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Thirman

Albrecht

Krueger

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Cigarette smoking is a leading risk factor for atherosclerosis. Endothelial ijur may be the initial event in this process. The carcinogenic metabolites of the polycyclic aromatic hydrocarbons found in cigarette smoke tars could cause this injury. We tested this model by examining the effect of 3-methyicholanthrene adminisration on aortic polycyclic aromatic hydrocarbon metabolism. Immunoblotting with a monoclonal antibody (mAb 1-7-1) specific for cytochromes CYPIA1 and CYPIA2 showed that aortic microsomes from treated, but not from control, animals contained CYPIA1; the CYPIA1 was primarily in the endothelium. Aortic microsomes from induced animals metabolized benzo[alpyrene (BaP) to the 7R,8S,9,10-tetrahydrotetrol-, 7,8-dhydrodiol-, 1,6 quinone-, 3,6 quinone-, 6,12 quinone-, 3-hydroxy-, and 9-hydroxy-BaP. mAb 1-7-1 inhibited the formation of the tetrahydrotetrol, the dihydrodiol-BaP, and the 3-hydroxy-BaP but did not inhibit the quinones or the 9-hydroxy-BaP. Arachidonic acid did not affect metabolism. These data suggest that the aortas of induced animals metabolize the BaP in cigarette smoke to carcinogenic and toxic products and that this metabolism may initiate vessel injury and lead to the accelerated atherosclerosis seen in cigarette smokers.Atherosclerotic vascular disease is the leading cause of death in developed nations. This process may be initiated by endothelial injury, which leads to the formation of a nidus for mononuclear cellular infiltration, cholesterol deposition, and platelet aggregation (1). Cardio-and cerebral vascular events are more frequent in individuals with hypertension, hyperlipidemia, and diabetes mellitus and in smokers. There has been some question of whether the increased incidence of vascular events seen in smokers is due to increased atherosclerosis or to alterations in other systems, such as the coagulation pathways. Although the latter may be important, the preponderance of evidence suggests that smokers have a significant increase in the incidence and degree of atherosclerosis in both the coronary and peripheral arteries (2).It is unclear which of the toxic products in the smokecarbon monoxide (3), nicotine (4), or the tars-are responsible for this acceleration. The tars, which include the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BaP), are possible candidates (5). Although BaP is not toxic, it is metabolically activated to highly toxic, mutagenic, and carcinogenic products-such as various epoxides and quinones. These toxic metabolites, if formed in the vessel wall, could initiate atherosclerosis by injuring the endothelial and muscle cells. If such is the case, then the arterial wall should catalyze their formation because it is unlikely that they could be transported to the peripheral vessels from the liver or lungs. Previous workers have found that a specific cytochrome P450, CYPIA1, catalyzes this metabolism in other organs (6, 7). In smooth muscle cells of young animals CYPIA1 is a constitutive form (8), but in older animals it is found in many or...

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“…The nature of the macrophage peroxidase is not known; however, the peroxidatic activity of PHS is likely since macrophages have the capacity to secrete relatively large amounts of prostaglandins (16 to reactive intermediates (34). In the current study, the bound to mtDNA forned a macromolecular complex that arachidonic acid-dependent activation of hydroquinone no longer migrated into either a neutral or alkaline gel.…”

Section: Discussionmentioning

confidence: 68%

Metabolism of phenol and hydroquinone to reactive products by macrophage peroxidase or purified prostaglandin H synthase.

Schlosser

Shurina

Kalf

1989

Environ Health Perspect

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Macrophages, an important cell-type of the bone marrow stroma, are possible targets of benzene toxicity because they contain relatively large amounts of prostaglandin H synthase (PHS), which is capable of metabolizing phenolic compounds to reactive species. PHS also catalyzes the production of prostaglandins, negative regulators of myelopoiesis. Studies indicate that the phenolic metabolites7of benzene are oxidized in bone marrow to reactive products via peroxidases. With respect to macrophages, PHS peroxidase is implicated, as in vivo benzene-induced myelotoxicity is prevented by low doses of nonsteroidal anti-inflammatory agents, drugs that inhibit PHS. Incubations of either '4C-phenol or '4C-hydroquinone with a lysate of macrophages collected from mouse peritoneum (> 95% macrophages), resulted in an irreversible binding to protein that was dependent upon H202, incubation time, and concentration of radiolabel. Production of protein-bound metabolites from phenol or hydroquinone was inhibited by the peroxidase inhibitor aminotriazole. Protein binding from '4C-phenol also was inhibited by 8 pM hydroquinone, whereas binding from '4C-hydroquinone was stimulated by 5 mM phenol. The nucleophile cysteine inhibited protein binding of both phenol and hydroquinone and increased the formation of radiolabeled water-soluble metabolites. Similar to the macrophage lysate, purified PHS also catalyzed the conversion of phenol to metabolites that bound to protein and DNA; this activation was both H202-and arachiodonic acid-dependent. These results indicate a role for macrophage peroxidase, possibly PHS peroxidase, in the conversion of phenol and hydroquinone to reactive metabolites and suggest that the macrophage should be considered when assessing the hematopoietic toxicity of benzene.

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Xenobiotic Metabolism by Prostaglandin Endoperoxide Synthetase

Cited by 81 publications

References 72 publications

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Metabolism of phenol and hydroquinone to reactive products by macrophage peroxidase or purified prostaglandin H synthase.

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