Chloroform nephrotoxicity

Smith, J.H. and Hook, J.B. (1983). Mechanism of chloroform nephrotoxicity. II. In vitro evidence for renal metabolism of chloroform in mice. Toxicol. Appl. Pharmacol. 70 480-485. 

Bailie MB, Smith JH, Newton JF, et al. 1984. Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys. Toxicol Appl Pharmacol 74 285-292. 

Kluwe WM, Hook JB. 1981. Potentiation of acute chloroform nephrotoxicity by the glutathione depletor diethyl maleate and protection by the microsomal enzyme inhibitor piperonyl butoxide. Toxicol Appl Pharmacol 59 457-466. 

Smith JH, Malta K, Sleight SD, et al. 1984. Effect of sex hormone status on chloroform nephrotoxicity and renal mixed function oxidases in mice. Toxicology 30 305-316. 

Kidneys have relatively low xenobiotic-metabolizing enzyme activities, and chemically induced nephrotoxicity has been assumed to be produced by toxic intermediates generated in the liver and transported to the kidney. If a single hepatic metabolite of chloroform produced both kidney and liver injury, species, strain, and sex differences in susceptibility to chloroform nephro- and hepatotoxicity should be similar. However, species, strain and sex differences in susceptibility to chloroform nephrotoxicity are not consistent with those of chloroform hepatotoxicity. In addition, several modulators of tissue xenobiotic-metabolizing activities alter... 

The mechanism of chloroform nephrotoxicity involves the oxidation of chloroform to trichloro-methanol by renal cytochrome P-450 isozymes (Figure 6). The trichloromethanol readily eliminates HCl to form the highly reactive toxicant phosgene (COCI2). The phosgene can (1) be detoxified by conjugation with two molecules of glutathione, (2) react with water to form two molecules of HCl and one molecule of CO2, or (3) covalently bind to renal macromolecules to disrupt cellular function and induce nephrotoxicity. 

Hewitt WR, Miyajima H, Cote M, et al. 1979. Acute alteration of chloroform-induced hepato- and nephrotoxicity by mirex and Kepone. Toxicol Appl Pharmacol 48 509-527. 

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

Ahmadizadeh M, Kuo C, Echt R, et al. 1984. Effect of polybrominated biphenyls, b-naphthoflavone and phenobarbital on arylhydrocarbon hydroxylase activities and chloroform-induced nephrotoxicity and hepatotoxicity in male C57BL/6J and DBA/2J mice. Toxicology 31 343-352. 

Branchflower RV, Nunn DS, Highet RJ, et al. 1984. Nephrotoxicity of chloroform Metabolism to phosgene by the mouse kidney. Toxicol Appl Pharmacol 72 159-168. 

Branchflower RV, Pohl LR. 1981. Investigation of the mechanism of the potentiation of chloroform-induced hepatotoxicity and nephrotoxicity by methyl n-butyl ketone. Toxicol Appl Pharmacol 61 407-413. 

Larson JL, Wolf DC, Butterworth BE. 1993. Acute hepatotoxic and nephrotoxic effects of chloroform in male F-344 rats and female B6C3Fi mice. Fundam Appl Toxicol 20(3) 302-315. 

Letteron P, Degott C, Labbe G, et al. 1987. Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice. Toxicol Appl Pharmacol 91 266-273. 

McMartin DN, OConnor JA Jr., Kaminsky LS. 1981. Effects of differential changes in rat hepatic and renal cytochrome p-450 concentrations on hepatotoxicity and nephrotoxicity of chloroform. Res Commun Chem Pathol Pharmacol 31 99-110. 

Pohl LR, George JW, Satoh H. 1984. Strain and sex differences in chloroform-induced nephrotoxicity Different rates of metabolism of chloroform to phosgene by the mouse kidney. Drug Metab Dispos 12 304-308. 

Smith JH, Hewitt WR, Hook JB. 1985. Role of intrarenal biotransformation in chloroform-induced nephrotoxicity in rats. Toxicology 79 166-174. 

Brown EM, Hewitt WR. 1984. Dose-response relationships in ketone-induced potentiation of chloroform hepato- and nephrotoxicity. Toxicol AppI Pharmacol 76 437-453. 

Chloroform is an anesthetic and solvent, which may be nephrotoxic and hepato toxic. It requires metabolic activation by cytochrome P-450, and male mice are more susceptible to the nephrotoxicity than females, which are more likely to suffer hepatic damage. The renal damage, proximal tubular necrosis, is accompanied by fatty infiltration. The metabolic activation, which may take place in the kidney, produces phosgene, which is reactive and can bind to critical proteins. 

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