Covalent binding of [14C]methoxychlor metabolite(s) to rat liver microsomal components

Bulger, William H.; Temple, Jane E.; Kupfer, David

doi:10.1016/0041-008x(83)90280-6

Cited by 33 publications

(17 citation statements)

References 22 publications

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“…During this reaction reactive metabolites, possibly free radicals, bind covalently to microsomal components (Bulger et al 1983). Antioxidants/free radical scavengers and sulfhydryl-containing compounds inhibit covalent binding of methoxychlor in human liver microsomes, suggesting that the reactive intermediate is a free radical (Bulger and Kupfer 1989).…”

Section: Discussionmentioning

confidence: 98%

“…The mechanism by which methoxychlor induces oxidative stress is not clear but it has been shown to be mediated by activation of microsomal mono-oxygenase, which is involved in the conversion of methoxychlor into its reactive metabolites (Bulger et al 1983). During this reaction reactive metabolites, possibly free radicals, bind covalently to microsomal components (Bulger et al 1983).…”

Section: Discussionmentioning

confidence: 98%

“…Increased oxidative stress has also been reported in the mitochondrial and microsome-rich fractions of rat testis (Latchoumycandane and Mathur 2002) as well as in epididymal sperm and various regions of the epididymis of rats following exposure to methoxychlor (Latchoumycandane et al 2002a). It has been shown that methoxychlor undergoes hepatic microsomal mono-oxygenase-mediated activation and the resultant reactive metabolites, possibly free radicals, bind covalently to microsomal components (Bulger et al 1983). Antioxidants/free radical scavengers and sulfhydryl-containing compounds inhibit covalent binding of methoxychlor in human liver microsomes, suggesting that the reactive intermediates are free radicals (Bulger and Kupfer 1989).…”

Section: Introductionmentioning

confidence: 93%

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Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor

Latchoumycandane

Mathur

2002

Archives of Toxicology

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The ability of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) to induce oxidative stress in various tissues of animals has been reported. The nature and mechanism of action of TCDD on the antioxidant system of sperm has not been studied. In the present study we have sought to investigate whether TCDD induces oxidative stress in the epididymal sperm of rats. Subchronic doses of TCDD (1, 10, and 100 ng/kg body weight per day) were administered orally to male Wistar strain rats for 45 days. After 24 h of the last treatment the rats were killed using diethyl ether. The epididymides were removed and cleared from the adhering tissues. Epididymal sperm were collected by cutting the epididymides into small pieces in Ham's F12 medium, and counted using a hemocytometer. The epididymal sperm counts in the TCDD-treated groups decreased in a dose-dependent manner from the control value of 8.2+/-0.14 x 10(8) to 5.31+/-0.15 x 10(8). Since a positive correlation (r=0.95; n=24) was observed between sperm count and DNA content of the epididymal sperm, DNA content was routinely used as an indicator of sperm count, and the results were expressed in terms of both protein and DNA. There was a significant decline in the activities of superoxide dismutase (40+/-2.17 to 27.1+/-0.76/mg protein and 32.41 to 18.07+/-0.76/mg DNA), catalase (2.49+/-0.13 to 2.03+/-0.05/mg protein and 2.01+/-0.05 to 1.35+/-0.05/mg DNA), glutathione reductase (71.2+/-3.87 to 48+/-1.79/mg protein and 57.58+/-1.52 to 31.94/mg DNA) and glutathione peroxidase (22.4+/-1.43 to 16.9+/-1.57/mg protein and 18.08+/-0.61 to 11.38+/-1.22/mg DNA) while there were increases in the levels of hydrogen peroxide (20.8+/-1.96 to 55.3+/-0.88/ mg protein and 16.18+/-1.88 to 36.87+/-0.88/ mg DNA) and lipid peroxidation (2.17+/-0.2 to 6.08/mg protein and 1.75+/-0.12 to 4.05+/-0.12/mg DNA) in the epididymal sperm. The results suggest that graded doses of TCDD elicit depletion of antioxidant defense system in sperm, indicating TCDD-induced oxidative stress in the epididymal sperm. In conclusion, the adverse effect on male reproduction in TCDD-treated rats may be due to the induction of oxidative stress in sperm.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 93%

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Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor

Latchoumycandane

Mathur

2002

Archives of Toxicology

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“…The pesticide methoxychlor is metabolized by liver microsomes into demethylated estrogenic products [ IO,1 1,311. We previously observed that methoxychlor, like TACE, can be metabolically activated to bind covalently to proteins [22,23]. However, by contrast to TACE [ 1.31, the reactive intermediate of methoxychlor (M*) did not bind to the exogenously added albumin (unpublished result).…”

Section: Resultsmentioning

confidence: 97%

Inactivation of the uterine estrogen receptor binding of estradiol during P‐450 catalyzed metabolism of chlorotrianisene (TACE)

Kupfer¹,

Bulger²

1990

FEBS Letters

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C~orot~an~ene (TACE) exhibits in vitro little or no binding to the uterine estrogen receptor (ER) but demonstrates potent estrogenic activity in vivo, indicating that TACE is a proestrogen/proantiestrogen.Our earlier studies demonstrated that the incubation of TACE with rat liver microsomes and NADPH generates a reactive intermediate (T*) which binds covalently to proteins. The current study examined the possibility that T* may inactivate the uterine ER. The incubation of TACE with rat liver microsomes and NADPH in the presence of rat uteri, under conditions which generate T*, markedly decreased the binding capacity of the ER for PH]estradiol (E& The evidence indicates that ER inactivation was probably due to irreversible (covalent) binding of T* to the E, binding site. The ~ssibility that the antiestrogenic action of TACE and of other triphenylethylenes involves such a novel mechanism is discussed.

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“…Moreover, methoxychlor exhibits reproductive toxicity in animals (9)(10)(11). Additionally, methoxychlor undergoes a P450 (CYP)-mediated metabolic activation, generating a reactive intermediate that binds covalently to proteins (12,13). In turn, this covalent binding could be the cause for the in vitro time-dependent inhibition/inactivation of certain CYP enzymes by methoxychlor, primarily that of CYP3A (14).…”

Section: Introductionmentioning

confidence: 98%

Mechanism of induction of rat hepatic CYP2B and 3A by the pesticide methoxychlor

Kupfer

1998

J. Biochem. Mol. Toxicol.

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Our earlier investigation demonstrated that methoxychlor treatment induced hepatic cytochrome P450 2B1/2B2 and 3A proteins in rats and enhanced their respective enzymatic activities. To determine the mechanism of the methoxychlor‐mediated induction and whether methoxychlor acts as a frank inducer and not merely by causing stabilization of the cytochrome P450 proteins or of their mRNAs, we assessed the effect of methoxychlor treatment on the transcriptional rate and mRNA levels of these hemeproteins by nuclear run‐on and northern blot analyses. Methoxychlor treatment markedly elevated the transcriptional rates of cytochrome P4502B1/2B2 and 3A. Also, higher levels of mRNA of these CYPs were observed. By contrast, mRNA levels of CYP1A1/1A2 were not affected. Using a nuclear run‐on method that apparently measures specifically the transcription initiation rate of CYP2B1 and 2B2, we observed that the transcriptional rate of 2B2 was increased substantially more than that of CYP2B1. This differential induction of CYP2B2 versus 2B1 may account for the discrepancy between the levels of induced CYP2B protein and the much lower‐than‐expected CYP2B‐mediated enzymatic activity observed in our earlier study. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 12: 315–323, 1998

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Covalent binding of [14C]methoxychlor metabolite(s) to rat liver microsomal components

Cited by 33 publications

References 22 publications

Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor

Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor

Inactivation of the uterine estrogen receptor binding of estradiol during P‐450 catalyzed metabolism of chlorotrianisene (TACE)

Mechanism of induction of rat hepatic CYP2B and 3A by the pesticide methoxychlor

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