Hepatotoxicity in Guinea Pigs Following Acute Inhalation Exposure to 1,1-Dichloro-2,2,2-Trifluoroethane

Marit, Gary B.; Dodd, Darol E.; George, Marilyn E.; Vinegar, Allen

doi:10.1177/019262339402200406

Cited by 30 publications

(12 citation statements)

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“…The fact that such correlations were not found in our previous study (Hoet et al 2001) might be explained by the narrower range of CMR values in that previous experiment, which did not include an induction protocol. Thus, the present study reports, for the first time, that differences in CYP2E1 activity may explain the notable variability in the response of the guinea-pig to HCFC-123 as reported previously by us (Hoet et al 2001) and others (Marit et al 1994;Lind Fig. 6 Centrilobular vacuolisation and necrosis of the intermediate zone of liver in a guinea-pig exposed to 5000 ppm HCFC-123 after 5% ethanol consumption (paraffin section stained with haematoxylin and eosin) Fig.…”

Section: Discussionsupporting

confidence: 78%

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Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs

Hoet

Buchet

Sempoux

et al. 2002

Archives of Toxicology

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HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane), a substitute for the banned chlorofluorocarbons (CFCs), is a structural analogue of the well-known hepatotoxicant halothane. The objectives of these experiments were to investigate (1) whether, like halothane, multiple exposure increases the risk of HCFC-123-induced liver toxicity, and (2) whether ethanol, a potent CYP2E1 inducer, potentiates the liver toxicity of HCFC-123. In experiment 1, male Hartley guinea-pigs were exposed twice a week to 5000 ppm HCFC-123 (4 h) during 3 weeks followed by 2 weeks recovery, and then re-exposed or not during 4 h to 5000 ppm HCFC-123. A group with a single exposure to 5000 ppm HCFC-123 and a control group were also included. In experiment 2, guinea-pigs received 5 or 10% ethanol in drinking water during 12 days before a single 4-h exposure to 5000 ppm HCFC-123. A group receiving 10% only, a group exposed once to 5000 ppm HCFC-123 but not pre-treated with ethanol and a control group were also included. In both experiments, the liver toxicity was assessed, 24 h post-exposure, by the serum activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICDH) as well as by histopathology. In experiment 2 the urinary excretion rate of the main metabolites trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) was assessed and CYP2E1 activity was measured by the chlorzoxazone metabolic ratio. Multiple exposure to 5000 ppm HCFC-123 did not cause greater liver damage than a single exposure (ALT, ICDH 3-fold control values). At this level of exposure the liver lesions were totally reversible within two weeks. Ethanol consumption produced CYP2E1 induction, increased urinary excretion of both HCFC-123 metabolites (more than 2-fold the rate measured in the non-induced group) and markedly increased the liver toxicity of HCFC-123 as shown by the serum liver enzyme activities (ALT 8.5-fold increase, ICDH 13-fold increase), and the histopathology. The necrosis was predominantly localised in the intermediate zone of the hepatic lobules with vacuolisation of the centrilobular zones. The effects associated with 10% ethanol pre-treatment were less marked than those observed with ethanol 5% and could be explained by the remaining blood ethanol levels causing an inhibition of HCFC-123 biotransformation. Significant correlations were obtained between the serum enzyme activities, the histopathology, the excretion rate of the metabolites and CYP2E1 activity. It can be concluded that (1) multiple exposure to HCFC-123 did not increase the liver toxicity of HCFC-123 in this experimental model, and (2) chronic ethanol consumption, known to be CYP2E1 inducer, strongly enhanced the biotransformation of HCFC-123 and its liver toxicity.

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Section: Discussionsupporting

confidence: 78%

“…Acute inhalation of HCFC-123 has also been found to produce hepatotoxicity in guinea-pigs (Marit et al 1994;Lind et al 1995;Hoet et al 2001). We recently reported that co-exposure to HCFC-124 does not significantly modify the hepatoxic potential of HCFC-123 (5000 ppm) in the guinea-pig (Hoet et al 2001).…”

Section: Introductionmentioning

confidence: 94%

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs

Hoet

Buchet

Sempoux

et al. 2002

Archives of Toxicology

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“…1 Acute exposure to HCFC-123 has been shown to produce severe hepatotoxicity in guinea pigs. 2 A single acute exposure to 1000 ppm of HCFC-123 for 4 hours can cause increases in aspartate aminotransferase and alanine aminotransferase levels compatible with hepatocellular necrosis. Increased liver weight, focal liver necrosis, induction of peroxisomal activity and hepatocellular adenomas have been found in subchronic studies in rats and dogs.…”

Section: Discussionmentioning

confidence: 99%

An outbreak of refrigerant-induced acute hepatitis in Hong Kong

et al. 2014

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“…Indeed, the liver damage and necrosis observed in animals (Marit et al 1994) and man (Hoet et al 1997;Takebayashi et al 1998), following acute or repeated exposure to HCFC-123, resemble those induced by its structural and metabolic analogue, the anaesthetic halothane. Tomasi et al (1983) demonstrated activation of halothane to free radicals, accompanied by cytotoxicity, in isolated rat hepatocytes under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Bioactivation and Cytotoxicity of 1,1‐Dichloro‐2,2,2‐trifluoroethane (HCFC‐123) in Isolated Rat Hepatocytes*

Ferrara

Zanovello

Bortolato

et al. 2001

Pharmacology & Toxicology

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Abstract:The bioactivation and cytotoxicity of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), a replacement for some ozone-depleting chlorofluorocarbons, were investigated using freshly isolated hepatocytes from non-induced male rats. A time-and concentration-dependent increase in the leakage of lactate dehydrogenase and a concentration-dependent loss of total cellular glutathione were observed in cells incubated with 1, 5 and 10 mM HCFC-123 under normoxic or hypoxic (about 4% O 2 ) conditions. Lactate dehydrogenase leakage was completely prevented by pretreating the cell suspension with the free radical trapper N-t-butyl-a-phenylnitrone. The aspecific cytochrome P450 (P450) inhibitor, metyrapone, totally prevented the lactate dehydrogenase leakage from hepatocytes, while two isoform-specific P450 inhibitors, 4-methylpyrazole and troleandomycin (a P450 2E1 and a P450 3A inhibitor, respectively), provided a partial protection against HCFC-123 cytotoxicity. Interestingly, pretreatment of cells with glutathione depletors, such as phorone and diethylmaleate, did not enhance the HCFC-123-dependent lactate dehydrogenase leakage. Two stable metabolites of HCFC-123, 1-chloro-2,2,2-trifluoroethane and 1-chloro-2,2-difluoroethene, were detected by gas chromatography/mass spectrometry analysis of the head space of the hepatocyte incubations carried out under hypoxic and, although at a lower level, also normoxic conditions, indicating that reductive metabolism of HCFC-123 by hepatocytes had occurred. The results overall indicate that HCFC-123 is cytotoxic to rat hepatocytes under both normoxic and hypoxic conditions, due to its bioactivation to reactive metabolites, probably free radicals, and that P450 2E1 and, to a lower extent, P450 3A, are involved in the process.

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Hepatotoxicity in Guinea Pigs Following Acute Inhalation Exposure to 1,1-Dichloro-2,2,2-Trifluoroethane

Cited by 30 publications

References 13 publications

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs

An outbreak of refrigerant-induced acute hepatitis in Hong Kong

Bioactivation and Cytotoxicity of 1,1‐Dichloro‐2,2,2‐trifluoroethane (HCFC‐123) in Isolated Rat Hepatocytes*

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