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

Abstract

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.

Long-term day-and-night rotating shift work poses a barrier to the normalization of alanine transaminase

“…The liver is a highly resilient organ, and the diseased liver, as represented by e-ALT serum levels, has been shown to recover and normalize in animal studies after the removal of hepatotoxic agents (Bruckner et al, 1986;Duncan et al, 1998;Hoet et al, 2002;Venkateswara Rao, 2006). This potential for recovery has been similarly demonstrated in humans after successful liver surgery (Jones et al, 1995;Watanapa, 1996).…”

“…The liver is a highly resilient organ that plays a vital role in nutrition and detoxification (Schmid, 1976), and surrogate markers for liver disease, such as elevated ALT (e-ALT) (Liu et al, 2012;Mohammad Ebrahim Ghamar-Chehreh, 2012;Ruhl & Everhart, 2009), are normalized within a relatively short period following liver repair (Bruckner et al, 1986;Duncan et al, 1998;Hoet et al, 2002;Jones et al, 1995;Venkateswara Rao, 2006;Watanapa, 1996). Therefore, the exposure to hazards in the workplace raises concerns when they are present as barriers to the normalization of e-ALT.…”

Characterization of Liver Injury Associated with Hypersensitive Skin Reactions Induced by Trichloroethylene in the Guinea Pig Maximization Test

“…Though the possible role of trichloroacetylated protein acting as an antigen is suggested by analogy with the hepatitis induced by 2,2-dichloro-1,1,1-trifluoroethane 21) . The reason why TCE, but not DNCB used as a positive control for GPMT, induced hepatic damage should be further investigated.…”

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

“…The effects, however, of the co-administration of the two drugs on hepatic levels of these enzymes remains unknown, and needs to be assessed in order to understand the effects of the frequent co-use of alcohol and nicotine on drug metabolism. Previous studies have shown that co-administration of ethanol with other drugs can potentiate the induction of CYP2E1, as well as its toxicity (Hoet et al, 2002;Kessova et al, 2001). …”