Vinylidene chloride: Its metabolism by hepatic microsomal cytochrome P-450 in vitro

Costa, Anita K.; Ivanetich, Kathryn M.

doi:10.1016/0006-2952(82)90425-7

Cited by 29 publications

(8 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results of these studies corroborate previous reports that covalent binding of DCE to liver microsomes is an NADPH-cytochrome P-450-dependent reaction (Costa & Ivanetich, 1982;Liebler et al, 1985;,Chen et al, 1983). When the incubation conditions used in our system were varied (Table I ) , we produced alterations in covalent binding by EUT microsomes similar to those reported by Liebler et al (1985) for microsomes from untreated rats: DCE covalent binding to microsomes was enhanced by the addition of NADH, and decreased by the absence of NADPH or by the addition of GSH.…”

Section: Discussionsupporting

confidence: 93%

“…This enhanced vulnerability of hyperthyroid rats to DCE has been proposed to be due to alterations in either the bioactivation or the detoxication phases of DCE metabolism (Jaeger et metabolites that covalently bind to cell constituents via NADPHcytochrome P-450-dependent oxidation (Costa & Ivanetich, 1982;Liebler et al, 1985), while detoxication of these reactive metabolites occurs via conjugation witti glutathione (GSH) or via further metabolism by such enzymes as alcohol dehydrogenase Liebler et al, 1985).…”

mentioning

confidence: 98%

See 1 more Smart Citation

Effect of Hyperthyroidism on the in Vitro Metabolism and Covalent Binding of 1,1-Dichloroethylene in Rat Liver Microsomes

Gunasena¹,

Kanz²

1997

Journal of Toxicology and Environmental Health

View full text Add to dashboard Cite

Hyperthyroidism potentiates the in vivo hepatotoxicity of I, 1-dichloroethylene (DCE) in rats, with a concomitant increase in ['4C]-DCE covalent binding. The enhanced injury produced in hyperthyroid livers by DCE could be due to alterations in either the bioactivation or detoxication phases of DCE metabolism. Previous in vitro studies suggested that hyperthyroidism did not potentiate DCE hepatotoxicity by increasing DCE oxidation to intermediates which were able to covalently bind. Several factors, however, that could contribute to the magnitude of DCE bioactivation or covalent binding were not examined. Our objectives were to characterize the effects of hyperthyroidism in male Sprague-Dawley rats on: (1 ) covalent binding of ["CI-DCE to microsomes and other subcellular fractions, (2) microsomal mixed-function oxidase (MFO) and glutathione S-transferase (CST) activities, and (3) inactivation of microsomal enzyme activities by presumptive DCE reactive intermediates. Hyperthyroid (HYPERT) and euthyroid (EUT) rats received 3 sc injections of thyroxine (100 pg/100 g) or vehicle, respectively, at 48-h intervals; microsomes and other subcellular fractions were isolated from HYPERT and EUT livers 24 h after the last injection. ['4C]-DCE-derived covalent binding was consistently greater in EUT than HYPERT microsomes. The absence of NADH, and the addition of low concentrations (0.1 and 0.5 mM), but not higher concentrations (>I mM), of glutathione (CSH) diminished covalent binding to a greater extent in HYPERT than EUT microsomes. Covalent binding in mitochondrial, nuclear, and cytosolic fractions of EUT and HYPERT livers was equivalent. Regression analysis of covalent binding to liver cell fractions from both EUT and HYPERT rats showed a significant correlation with P-450 content. Hyperthyroidism decreasedmicrosomal, but not mitochondria/, cytochrome P-450 content, and MFO activities for 7-ethoxycoumarin and benzphetamine were similarly decreased. Hyperthyroidism also diminished microsomal GST activity, and altered CST kinetics for both . The magnitude of inactivation of MFO and GST activities in the presence of DCE (presumably by DCE reactive intermediates) was comparable between EUT and HYPERT microsomes. When covalent binding was standardized to cytochrome P-450 concentrations in microsomes and mitochondria, HYPERT fractions exhibited slightly greater covalent binding than EUT fractions, suggesting that hyperthyroidism does not reduce the capacity of P-450 hemoproteins to bioactivate DCE. Thus, potentiation of DCE hepatotox,'city by hyperthyroidism may be predominantly due to diminished Phase I1 constituents, and major increases in reactive intermediate/coniu~ates , " that covalently bind to and impair critical cellular molecules.The i n vivo hepatotoxicity of 1,l-dichloroethylene (DCE) in rats i s potentiated by hyperthyroidism Jaeger et al., 1977;Kanz et al., 1988Kanz et al., , 1994. This enhanced vulnerability of hyperthyroid rats to DCE has been proposed to be due to alterations in either the bioactivation or the...

show abstract

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 98%

Effect of Hyperthyroidism on the in Vitro Metabolism and Covalent Binding of 1,1-Dichloroethylene in Rat Liver Microsomes

Gunasena¹,

Kanz²

1997

Journal of Toxicology and Environmental Health

View full text Add to dashboard Cite

show abstract

“…No metabolic activation of VDC in mouse kidney microsomes, except in mice pretreated with inducers of P450, has been observed, however (Costa and Ivanetich 1982;Okine and Gram 1986). In analogy with previous results, decreased renal covalent binding of VDC, although not significant, was observed following pretreatment with the P450 inhibitor piperonyl butoxide, indicating that a piperonyl butoxidesusceptible form of P450 may be involved in the process leading to covalent binding in the kidney in vivo (Okine et al 1985).…”

Section: Kidneysupporting

confidence: 74%

Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice

et al. 1993

View full text Add to dashboard Cite

Autoradiography of mice injected i.p. with 14C-labelled 1,1-dichloroethylene (vinylidene chloride, VDC) in C57B1/6 mice revealed a selective covalent binding of radioactivity in the proximal tubules, in the midzonal parts of the liver lobules and in the mucosa of the upper and lower respiratory tract. Since VDC is a renal carcinogen in male mice the effects of compounds modulating biotransformation and glutathione (GSH) levels on the renal covalent binding were examined following a single i.p. dose of 14C-VDC. Most pretreatments did not influence the level of binding but treatment with buthionine sulphoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase and glutathione (GSH)-depleting agent, increased the renal covalent binding of VDC three-fold. Histopathological examination of kidneys in BSO-pretreated male mice given single i.p. injections of subtoxic doses of VDC (25 and 50 mg/kg) showed necrosis in the proximal tubules (S1 and S2 segments) 24 h following administration. In mice given VDC only, no significant lesions in the kidneys were observed. The severe renal toxicity of VDC in BSO-pretreated mice is suggested to be related to metabolic activation of VDC in the proximal tubules, resulting in further GSH depletion and covalent binding.

show abstract

“…Metabolism of 1, 1-DCE by the liver apparently occurs by a two-phase process with an initial NADPHcytochrome P-450-mediated activation of the compound to electrophilic intermediates (10), followed mainly by a glutathione (GSH) S-transferase mediated detoxification of these intermediates. Products of GSH conjugation are the major urinary metabolites of 1,1-DCE (11).…”

Section: Biochemical Alterationsmentioning

confidence: 99%

1,1-Dichloroethylene: An Apoptotic Hepatotoxin?

Reynolds¹,

Kanz²,

Chieco³

et al. 1984

Environmental Health Perspectives

View full text Add to dashboard Cite

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) andBrogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.Within 2 hr after 1,1-dichloroethylene administration, the following phenomena occur in livers of fasted rats: dilation and disruption of bile canaliculi, plasma membrane invagination and loss of microvilli, cytoplasmic vacuolation, and loss of density in mitochondrial matrices. Early, selective loss of enzyme activities was localized by histochemical staining to bile canalicular, and inner and outer mitochondrial membranes. Biliary permeability to inulin increased, a change suggestive of the breakdown of junctions between hepatocytes. Endoplasmic reticulum and lysosomes appeared spared. In addition, scattered, individual hepatocytes exhibited changes characteristic of apoptosis by 2 hr: chromatin aggregation and margination, nucleolar coarse granulation and enlargement, rounded blebs and proturberances on cell surfaces, and the separation of these cells from surrounding parenchyma. In contrast, evidence of plasma membrane leakiness to K+, Ca2+ and soluble cytoplasmic enzymes was not detected until after 2 hr. Based on these observations, we propose that 1,1-dichloroethylene may initiate apoptosis-like cell degradation in selected parenchymal cells prior to or coincident with centrolobular necrosis. Apoptosisis a rapid type of cell death which is considered by Kerr and colleagues (1,2) to differ distinc-

show abstract

Vinylidene chloride: Its metabolism by hepatic microsomal cytochrome P-450 in vitro

Cited by 29 publications

References 27 publications

Effect of Hyperthyroidism on the in Vitro Metabolism and Covalent Binding of 1,1-Dichloroethylene in Rat Liver Microsomes

Effect of Hyperthyroidism on the in Vitro Metabolism and Covalent Binding of 1,1-Dichloroethylene in Rat Liver Microsomes

Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice

1,1-Dichloroethylene: An Apoptotic Hepatotoxin?

Contact Info

Product

Resources

About