Nephrotoxicity, chloroform induced

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. 

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. 

Male and female animals of the same strain and species usually react to toxicants similarly. It must be borne in mind, however, that there are marked differences in the hormonal makeup between sexes, and this can result in notable differences in responses. Chloroform produces damage to liver and kidney in humans and mice. In mice, however, chloroform produces nephrotoxicity only in males. Furthermore, administration of testosterone (male hormone) to the female mouse followed by chloroform results in kidney damage. Clearly, there are androgen (male) receptors in the kidney that sensitize males to chloroform-induced nephrotoxicity. In rats, exposure to the hydrocarbon decalin results in a renal nephropathy and tumor formation in the male but not female, and this is associated with an ot2-globulin protein accumulation. Treatment of females with testosterone followed by decalin also produces renal toxicity and protein accumulation. These examples demonstrate that kidney function differs between the sexes and, consequently, toxic manifestations will vary between males and females. 

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). 

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. 

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. 

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. 

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

Cytochrome P-450 and cysteine conjugate p-lyse are primarily localized in the proximal tubules, and these enzymes also contribute to the susceptibility of the proximal tubule to toxicant injury. Specifically, widely used industrial solvents such as chloroform produce tubular nephrotoxicity via cytochrome P-450 activation, and haloaUcanes and haloalkenes (e.g. trichloroethylene) are rendered toxic by cysteine conjugate (3-lyse activation [24,24a]. In addition, overdoses of acetaminophen (APAP) cause nephrotoxicity that is characterized by proximal tubular necrosis [25]. APAP undergoes cytochrome P-450-mediated activation to produce a toxic electrophile, N-acetyl-p-benzoquinon-eimine (NAPQI) [25a]. Although NAPQI is extremely reactive, it is detoxified by conjugation with reduced GSH unless NAPQI is formed in excess of the cellular capacity for GSH conjugation. The excess NAPQI is available to bind to critical cellular proteins and to induce oxidative stress, resulting in disruption of cellular homeostasis and tubular injury [26]. 

The mechanism is believed to involve metabolic activation in the kidney itself. Thus, when radiolabelled chloroform was given to mice, in the kidney the radiolabel was localized in the tubular cells which were necrotic. Certain microsomal enzyme inducers such as 3-methylcholanthrene decreased the nephrotoxicity but not hepatotoxicity of chloroform, and phenobarbital pretreatment had no effect on nephrotoxicity but increased hepatotoxicity. Pretreatment with polybrominated biphenyls, however, increased toxicity to both target organs and also increased mixed function oxidase activity in both. In vitro studies have shown that microsomal enzymemediated metabolism of chloroform to C02 occurs in... 

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