Bioactivation of xenobiotics by prostaglandin H synthase

Smith, Bill J.; Curtis, John F.; Eling, Thomas E.

doi:10.1016/0009-2797(91)90108-j

Cited by 82 publications

(24 citation statements)

References 71 publications

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“…In light of the nephrotoxicity and teratogenicity observed after TBZ administration, PGS was selected as a mammalian model enzyme to probe the oxidative metabolism of 5-OHTBZ. PGS is a microsomal hemoprotein that catalyzes the oxidation of arachidonic acid to prostaglandin H 2 in reactions which use both cyclooxygenase and peroxidase activities (Smith et al, 1991;O'Brien, 2000;Vogel, 2000). During this process, the enzyme activities generate enzyme and substrate-derived free radicals that can simultaneously co-oxidize numerous xenobiotics.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

Dalvie¹,

Smith²,

Deese³

et al. 2006

Drug Metab Dispos

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Thiabendazole (TBZ) (Fig. 1) is a broad-spectrum antihelmintic used for treatment of parasitic infections in animals and humans and an agricultural fungicide for postharvest treatment of fruits and vegetables (Walton et al., 1999;Groten et al., 2000). It is recognized as a potent nephrotoxin that causes tubular necrosis, leading to severe kidney damage and a teratogen that results in impairment of mouse limb development and selective toxicity to the embryo (Ogata et al., 1984;Mizutani et al., 1990;Tada et al., 1992;Fujitani et al., 1999). Irreversible binding of TBZ-related radioactivity to macromolecules and tissue protein in the mouse embryo has also been observed after oral dosing of [ 14 C]TBZ to pregnant mice (Yoneyama and Ichikawa, 1986). In humans, several isolated cases of hepatotoxicity, such as intrahepatic cholestasis or micronodular cirrhosis, have also been reported after TBZ administration (Manivel et al., 1987;Bion et al., 1995). It is currently believed that TBZ-induced nephrotoxicity is a result of P450-dependent oxidative cleavage of the thiazole moiety in TBZ to a proximate toxicant, thioformamide ( Fig. 1) (Mizutani et al., 1994). However, the mechanisms responsible for TBZ-induced hepatotoxicity in humans and teratogenicity in preclinical species are not clear.TBZ is extensively metabolized in animals and humans (Tocco et al., 1966). The primary route of metabolism is the CYP1A2-catalyzed formation of 5-hydroxythiabendazole (5-OHTBZ), which is further converted to a glucuronide and a sulfate conjugate and is eliminated in the urine and bile (Wilson et al., 1973;Rey-Grobellet et al., 1996; Coulet et al., 1998a,b). Other metabolites such as 4-hydroxythiabendazole, 2-acetylbenzimidazole, N-methylthiabendazole, and benzimidazole have also been detected (Fujitani et al., 1991). Recent studies by Coulet et al. (2000) have shown good correlation in the covalent binding of the radiolabel to proteins and the formation of 5-OHTBZ in incubations of [ 14 C]TBZ with cultured human and rabbit hepatocytes. These studies have also shown that treatment of CYP1A2-expressing liver cells with isolated [14 C]5-OHTBZ leads to significant covalent binding of the radiolabel (Coulet et al., 2000). Furthermore, 5-OHTBZ has been described to possess the same teratogenic potential as the parent drug TBZ, as demonstrated in a limb-bud culture system (Tsuchiya et al., 1987

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Section: Discussionmentioning

confidence: 99%

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

Dalvie¹,

Smith²,

Deese³

et al. 2006

Drug Metab Dispos

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“…As arachidonic acid metabolism has been shown to be involved in the bladder carcinogenic process [3][4][5], it is important to know the regulatory mechanism of PG syn thesis in the urinary bladder epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…We have already shown the presence of arachidonic acid at high concentrations within the plasma membrane of rat bladder epithelium and suggested an important role of arachidonic acid metabolism in the physiological func tion of urinary bladder epithelium [1], Furthermore, precancerous rat bladder epithelium, which was induced by N-butyl-N-(4-hydroxybutyl)-nitrosoamine, had more ara chidonic acid than normal rat bladder epithelium [1], Several reports suggest that arachidonic acid metabolism may be implicated in the carcinogenic process, that is, in its initiation and promotion [2], Urinary bladder carcino gens such as benzidine [3], 2-amino-4-(5-nitro-2-furyl)thiazole [4] and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) [5] are changed to their active forms by co-oxidation metabolism during prostaglandin (PG) syn thesis. It is suggested that metabolic activation by bladder PGH2 synthase may be involved in the genesis of chemi cally induced urinary bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

Effects of Thiols on Prostaglandin Synthesis in Bovine Bladder Epithelium

Mimata¹,

Tanigawa²,

Takeshita³

et al. 1993

Urol Int

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The regulation of prostaglandin (PG) synthesis was characterized in microsomes of bovine bladder epithelium. Coenzyme A (CoA) and its metabolite cysteamine drastically decreased total PG synthesis. Furthermore, CoA inhibited solubilized cyclooxygenase which was precipitated by anti-cyclooxygenase antibody. Reduced glutathione (GSH) slightly increased total PG production and changed the pattern of PG synthesis. Other thiols, cysteine and ergothioneine, did not change total PG production. None of the thiols stimulated the incorporation of arachidonic acid into the phospholipid fraction. These findings suggest that CoA may directly regulate cyclooxygenase activity and GSH may subsequently change the pattern of PG production in bovine bladder epithelium.

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“…Oxidations of these compounds, termed cosubstrates, were catalyzed by the peroxidase activity of PHS. Investigations from several laboratories on activation of carcinogenic N-arylamines via PHS-mediated oxidations have recently been reviewed (2,3). PHS catalyzed one electron (le-)-oxidation of N-2-fluorenamine (2-FA) to nitrogen-centered free radicals, which yielded dimeric and polymeric products and 2-nitrofluorene (2-NO2F).…”

mentioning

confidence: 99%

Peroxidative metabolism of carcinogenic N-arylhydroxamic acids: implications for tumorigenesis.

Malejka-Giganti

Ritter

1994

Environ Health Perspect

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Peroxidative oxidations of chemical carcinogens including N-substituted aryl compounds could result in their metabolic activation because the products react with cellular molecules and lead to cytotoxicity, mutagenicity, and carcinogenicity. In vivo, peroxidative activities are chiefly of neutrophilic leukocyte origin. Neutrophils may be attracted to the site(s) of exposure to carcinogen and, via phagocytosis and respiratory burst, release oxidants that catalyze carcinogen activation and/or cause DNA damage. Our studies, presented herein, concern oxidations of carcinogenic N-arylhydroxamic acids, N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA), and N-hydroxy-N-2-fluorenylbenzamide (N-OH-2-FBA), by enzymatic and chemical systems simulating those of neutrophils, myeloperoxidase and hydrogen peroxide (H202) ± halide, and hypohalous acid and halide at the physiologic concentrations (0.1 M Cl and/or 0.1 mM Br) and the pH (4-6.5) of phagocytosis. Studies also concern oxidations of the hydroxamic acids by rat peritoneal neutrophils stimulated to undergo respiratory burst and release myeloperoxidase in medium-containing 0.14 M Cl-± 0.1 mM Br-. The metabolites formed in the presence of exogenous H202 are consistent with two peroxidative mechanisms: one electron-oxidation to a radical that dismutates to equimolar 2-nitrosofluorene (2-NOF) and the ester of the respective hydroxamic acid and halide-dependent oxidative cleavage, especially efficient in the presence of Br, to equimolar 2-NOF and the respective acyl moiety. 2-NOF and the esters undergo further enzymatic and nonenzymatic conversions to unreactive products and/or may bind to cellular macromolecules. The results suggest that peroxidative metabolism of N-arylhydroxamic acids by neutrophils, yielding the potent direct mutagen 2-NOF and the electrophilic esters, occurs in vivo and is involved in the activation and thus local tumorigenicities of the hydroxamic acids at the site(s) of application.

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Bioactivation of xenobiotics by prostaglandin H synthase

Cited by 82 publications

References 71 publications

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

Effects of Thiols on Prostaglandin Synthesis in Bovine Bladder Epithelium

Peroxidative metabolism of carcinogenic N-arylhydroxamic acids: implications for tumorigenesis.

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