Phosgene: A metabolite of chloroform

Pohl, Lance R.; Bhooshan, B.; Whittaker, Noel F.; Krishna, Gopal

doi:10.1016/0006-291x(77)91166-4

Cited by 205 publications

(50 citation statements)

References 11 publications

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“…BDCM induces renal toxicity in rats and hepatic toxicity in mice (10)(11)(12). Both chemicals have been shown to be metabolized by cytochrome P450, although the active metabolite has only been identified for CHCl3 (13)(14)(15). BDCM (but not CHCl3) has been demonstrated to be mutagenic (16).…”

Section: Introductionmentioning

confidence: 99%

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Lipsky

Skinner

O’Connell

1993

Environ Health Perspect

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We have been investigating the actions of chloroform (CHC13) and bromodichloromethane (BDCM) in rat kidney after different routes of exposure. Male F344 rats were exposed by gavage with corn oil or water as the diluting vehicle. All experiments lasted 30 days with gavage exposures 5 days per week for 4 weeks (20 doses). All animals were injected IP with bromodeoxyuridine (BrdU) 3 times over a 6-day period at 50 mg/kg/injection. Kidney tissue was fixed and slides were stained with hematoxylin and eosin for routine viewing and by the PAP (peroxidaseantiperoxidase) technique using anti-BrdU to label cells in DNA synthesis. There were no significant changes in gross parameters evaluated between the control rats and the rats exposed to CHCl3 or BDCM. Rats exposed via corn oil gavage to CHC13 displayed a segment-specific epithelial cell necrosis (6/6 high dose, 2/6 low dose). The lesions were primarily localized to the second segment of the proximal tubule, although some spread to cells in the first segment was occasionally observed. No histologic lesions were observed in the kidneys of rats exposed to BDCM.Preliminary results indicate a significant increase in DNA synthesis in the CHCI3-treated rats and a slight increase in DNA synthesis in BDCM-treated rats with corn oil as the diluent. The increase in BrdU labeling was primarily in cells of the S2 segment of the proximal tubule and interstitial cells of CHC13-exposed animals and in cells of the S3 segment of BDCM-exposed animals. The rats exposed using water as the vehicle did not show significant pathology (except for one rat in the high-dose CHC13 group, which had mild necrosis of proximal tubule epithelium). There were no changes in DNA synthesis in the CHCL3-treated rat kidneys when water was used as the vehicle. There was a slight increase in total DNA synthesis in the BDCM-treated rat kidneys, and the increase was mainly in the third segment of the proximal tubule. These data indicate differences in histopathologic alterations and levels of DNA synthesis that appear to depend on the vehicle that the chemicals were dissolved in and/or the route of administration. CHC13-induced pathologic alterations were more severe in the animals exposed by corn oil gavage. BDCM, an established renal carcinogen in rats, failed to induce any histopathologic alterations under the different experimental conditions of this study.

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Section: Introductionmentioning

confidence: 99%

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Lipsky

Skinner

O’Connell

1993

Environ Health Perspect

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“…1). Extensive in vitro and in vivo studies on rodents have demonstrated that chloroform may be metabolized oxidatively to trichloromethanol, which spontaneously decomposes to the electrophilic phosgene (Mansuy et al, 1977;Pohl et al, 1977). COCl 2 is highly reactive and binds covalently to cell components containing nucleophilic groups, including proteins, phospholipid (PL) polar heads, and reduced glutathione (Pohl et al, 1981;Testai et al, 1990;De Biasi et al, 1992;Gemma et al, 1996;Vittozzi et al, 2000).…”

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confidence: 99%

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Gemma¹,

Vittozzi²,

Testai³

2003

Drug Metab Dispos

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ABSTRACT:The oxidative and reductive cytochrome P450 (P450)-mediated chloroform bioactivation has been investigated in human liver microsomes (HLM), and the role of human P450s have been defined by integrating results from several experimental approaches: cDNA-expressed P450s, selective chemical inhibitors and specific antibodies, correlation studies in a panel of phenotyped HLM. HLM bioactivated CHCl 3 both oxidatively and reductively. Oxidative reaction was characterized by two components, suggesting multiple P450 involvement. The high affinity process was catalyzed by CYP2E1, as clearly indicated by kinetic studies, correlation with chlorzoxazone 6-hydroxylation (r ‫؍‬ 0.837; p < 0.001), and inhibition by monoclonal antihuman CYP2E1 and 4-methylpyrazole. The low affinity phase of oxidative metabolism was essentially catalyzed by CYP2A6. This conclusion was supported by the correlation with coumarin 7-hydroxylase (r ‫؍‬ 0.777; p < 0.01), inhibition by coumarin and by the specific antibody, in addition to results with heterologously expressed P450s. Chloroform oxidation was poorly dependent on pO 2 , whereas the reductive metabolism was highly inhibited by O 2 . The production of dichloromethyl radical was significant only at CHCl 3 concentration >1 mM, increasing linearly with substrate concentration. CYP2E1 was the primary enzyme involved in the reductive reaction, as univocally indicated by all the different approaches. The reductive pathway seems to be scarcely relevant in the human liver, since it is active only at high substrate concentrations, and in strictly anaerobic conditions. The role of human CYP2E1 in CHCl 3 metabolism at low levels, typical of actual human exposure, provides insight into the molecular basis for eventual difference in susceptibility to chloroform-induced effects due to either genetic, pathophysiological, or environmental factors.

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“…1 mediated oxidation of APAP but also to its cytochrome P-450-independent deacetylation which is not responsible for APAP-induced nephrotoxicity in normal SD rats. In addition, since there were no differences in the severity of gentamicin- (Tarloff and Goldstein, 1994), chloroform- (Pohl et al, 1977;Kluwe and Hook, 1981), or 45 minischemia/reperfusion-induced renal lesions (Arnold et al, 1986;Shapiro et al, 1987Shapiro et al, , 1989Mourelle et al, 1991) between the non-pretreated and the fructose-pretreated rats (Ishida et al, 1997a), alterations in APAP-specific pharmacokinetics and metabolism may play an important role in enhancement of APAP nephrotoxicity in fructosepretreated rats.…”

Section: Effects Of Hypertriglyceridemia On Apap-induced Hepatorenal mentioning

confidence: 99%

Diabetes and hypertriglyceridemia modify the mode of acetaminophen-induced hepatotoxicity and nephrotoxicity in rats and mice

Doi

Ishida

2009

J. Toxicol. Sci.

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Phosgene: A metabolite of chloroform

Cited by 205 publications

References 11 publications

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Diabetes and hypertriglyceridemia modify the mode of acetaminophen-induced hepatotoxicity and nephrotoxicity in rats and mice

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