Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: a dose-effect study

The relationship among dose, metabolism and hepatotoxicity in mice which resulted from subchronic exposure to the chlorinated solvents trichloroethylene (TRI) and perchloroethylene (PER) were examined. Male Swiss-Cox mice received either TRI (0 to 3200 mg/kg/day) of PER (0 to 2000 mg/kg/day) in corn oil by gavage for 6 weeks. Urinary metabolites from individual mice were quantified to estimate the extent to which each compound was metabolized. Four parameters of hepatotoxicity were assessed: liver weight, triglycerides, glucose-6-phosphatase (G6P) activity, and SGPT activity. TRI significantly affected liver weight and G6P activity; PER affected all four parameters. The metabolism of TRI was linearly related to dose through 1600 mg/kg, but then became saturated. The metabolism of PER was saturable. The dose-effect curves of the affected hepatotoxicity parameters of both compounds were nonlinear and resembled the dose-metabolism graph of the corresponding solvent. Plots of the hepatotoxicity data of each compound against total urinary metabolites were linear in all cases, suggesting that the hepatotoxicity of both PER and TRI in mice is directly related to the extent of their metabolism. This pattern is consistent with formation of the toxic intermediate in the primary metabolic pathway of each compound.     

Ethanol-induced enhancement of trichloroethylene metabolism and hepatotoxicity: difference from the effect of phenobarbital

Male Wistar rats pretreated with ethanol (2.0 g in 80 ml liquid diet/day for 3 weeks) or phenobarbital (PB, 80 mg/kg/day ip for 4 days) were exposed by inhalation to 500, 1000, 2000, 4000, or 8000 ppm trichloroethylene (TRI) for 2 or 8 hr, and the blood concentration of TRI and the urinary concentration of TRI metabolites (trichloroethanol (TCE) and trichloroacetic acid (TCA] were determined at various times. Plasma glutamic-pyruvic transaminase (GPT) activity was measured 22 hr after the end of exposure as an indicator of hepatic damage. Both ethanol and PB enhanced TRI metabolism as evidenced by accelerated disappearance of TRI from the blood and increased excretion of total trichloro compounds (TCE + TCA) in the urine. However, the effects of ethanol and PB were different from each other: ethanol markedly enhanced the metabolism particularly at TRI concentration of 2000 ppm or lower, whereas PB enhanced it only at 4000 ppm or higher. This difference was also reflected in the effect of TRI on liver: ethanol potentiated TRI hepatotoxicity more markedly than did PB when TRI concentration remained 2000 ppm or lower, whereas PB potentiated the toxicity more markedly than ethanol when the concentration was 4000 ppm or higher. It is noteworthy that ethanol potentiated TRI hepatotoxicity at a TRI concentration as low as 500 ppm. The severity of hepatic damage expressed by plasma GPT activity essentially paralleled the urinary excretion rate of total trichloro compounds during and 4 hr after exposure (r = 0.87 to 0.93). Compared between the contribution of concentration and duration of exposure to the toxicity, a higher concentration of TRI tended to cause more severe liver damage to PB-treated rats than did a prolonged period of exposure, whereas the toxicity in ethanol-treated rats was generally more marked in rats exposed to TRI for a longer period than in rats exposed to a higher concentration.     

Modulation of hepatic and renal metabolism and toxicity of trichloroethylene and perchloroethylene by alterations in status of cytochrome P450 and glutathione

The relative importance of metabolism of trichloroethylene (Tri) and perchloroethylene (Perc) by the cytochrome P450 (P450) and glutathione (GSH) conjugation pathways in their acute renal and hepatic toxicity was studied in isolated cells and microsomes from rat kidney and liver after various treatments to modulate P450 activity/expression or GSH status. Inhibitors of P450 stimulated GSH conjugation of Tri and, to a lesser extent, Perc, in both kidney cells and hepatocytes. Perc was a more potent, acute cytotoxic agent in isolated kidney cells than Tri but Perc-induced toxicity was less responsive than Tri-induced toxicity to modulation of P450 status. These observations are consistent with P450-dependent bioactivation being more important for Tri than for Perc. Incubation of isolated rat hepatocytes with Tri produced no acute cytotoxicity in isolated hepatocytes while Perc produced comparable cytotoxicity as in kidney cells. Modulation of P450 status in hepatocytes produced larger changes in Tri- and Perc-induced cytotoxicity than in kidney cells, with non-selective P450 inhibitors increasing toxicity. Induction of CYP2E1 with pyridine also markedly increased sensitivity of hepatocytes to Tri but had little effect on Perc-induced cytotoxicity. Increases in cellular GSH concentrations increased Tri- and Perc-induced cytotoxicity in kidney cells but not in hepatocytes, consistent with the role of GSH conjugation in Tri- and Perc-induced nephrotoxicity. In contrast, depletion of cellular GSH concentrations moderately decreased Tri- and Perc-induced cytotoxicity in kidney cells but increased cytotoxicity in hepatocytes, again pointing to the importance of different bioactivation pathways and modes of action in kidney and liver.     

Cytotoxicity of trichloroethylene and perchloroethylene on normal human epidermal keratinocytes and protective role of vitamin E

Trichloroethylene (TCE) and perchloroethylene (PERC), the most common alkenyl halides, have been extensively used in industry, and can cause skin damage. To evaluate their cytotoxic potential on skin, the effects of these agents on the normal human epidermal keratinocytes (NHEK) were investigated. Their action on cell viability, membrane integrity and lipid peroxidation (LPO) was assessed by neutral red uptake (NRU) assay, lactate dehydrogenase (LDH) release test and measurement of malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. In addition, the protective effect of antioxidatant vitamin E on the cytotoxicity was also studied. Incubation of NHEK with various concentrations (0.01-31.6 mM) of TCE or PERC caused a dose-dependent decrease in cell viability, with 80% reduction at 31.6 mM. NR50 values from the cytotoxicity assay was found to be 4.53 and 2.16 mM for TCE and PERC, respectively. A time- and concentration- dependent release of LDH were observed at 1, 2, 3, 4 h after cells were exposed to different doses of TCE or PERC. These agents also caused an increase of MDA, whilst an inhibition of SOD activity, in a concentration-dependent manner. Pre-treatment of the cells with vitamin E at 10-200 mM dose-dependently attenuated the cytotoxic effect of TCE or PERC. Pre-treatment with vitamin E also reversed subsequent TCE or PERC-induced release of LDH, elevation of lipid peroxidation and decline of anti-oxidant enzyme activities. These results suggest that TCE and PERC could induce cytotoxicity to NHEK associated with oxidative stress and antioxidatant vitamin E could effectively protect NHEK from TCE- or PERC-induced cytotoxicity, which may be associated to the superoxide scavenging effect and enhancement of anti-oxidant enzyme activities.     

Effects of trichloroethylene and perchloroethylene on muscle contractile responses and epithelial prostaglandin release and acetylcholinesterase activity in swine trachea.

Trichloroethylene (TCE) and perchloroethylene (PERC) have been reported to induce respiratory complications such as airway hyperactivity and asthma. The present study was designed to investigate their influence on smooth muscle contraction and epithelial release of prostanoids in swine trachea. Results showed that TCE and PERC exposure did not alter the basal tone of tracheal smooth muscle. However, TCE and PERC concentration-dependently increased both ACh-induced and high K+-induced muscle contraction. In addition to potentiation of muscle contractile responses evoked by acetylcholine or histamine, pretreatment of smooth muscle with PERC at higher concentration significantly suppressed the relaxant activity of beta-adrenergic agonists. The epithelial prostaglandin (PG)E2, but not PGD2, release from tracheal epithelium was significantly increased by TCE and PERC. In addition, the acetylcholinesterse (AChE) activity of tracheal epithelia was reduced by TCE and PERC. In conclusion, our results suggest that the enhancement of spasmogen-evoked muscle contractile responses and epithelial PGE2 secretion, as well as reduction of epithelial AChE activity, may participate in airway impairment and hyperresponsiveness after TCE and PERC exposure.     

Oxidative stress and DNA damage in Fischer rats following acute exposure to trichloroethylene or perchloroethylene

Oxidative DNA damage is emerging as an biomarker of effect in studies assessing the health risks of occupational chemicals. Trichloroethylene (TCE) and perchloroethylene (PERC) are used in the dry cleaning industry and their metabolism can produce reactive oxygen compounds. The present study examined the potential for TCE and PERC to induce oxidative DNA damage in rats that was detectable as increased urinary excretion of 8-hydroxydeoxyguanosine (8OHdG). Thiobarbaturic acid reactive substances (TBARS) and 8-epiprostaglandin F2alpha (8epiPGF) were also measured as biomarkers of increased oxidative stress. Male Fischer rats were administered a single i.p. injection of 0, 100, 500, or 1000 mg/kg of PERC or TCE. Control rats received only vehicle (1:4 v/v of Alkamuls/water). A positive control group received 100 mg/kg 2-nitropropane (2NP). Rats were sacrificed 24 h after dosing. In rats receiving 2NP or TCE but not PERC, TBARS and the 8OHdG/dG ratios were significantly elevated in liver. Lymphocyte 8OHdG/dG was not affected significantly by 2NP, TCE or PERC. In rats receiving 2NP, urinary excretion of 8OHdG and 8epiPGF2 were significantly increased. In rats receiving TCE or PERC, significant increases in 8epiPGF2 or 8OHdG were not evident. Results indicate that a single high dose of TCE, but not PERC, can induce an increase in oxidative DNA damage in rat liver. However, the usefulness of 8OHdG as a biomarker of TCE-induced oxidative DNA damage is questionable.     

Effect of ethanol on the metabolism of trichloroethylene

Trichloroethylene (TCE) is metabolized to chloral hydrate (CH) by the cytochrome P-450 monooxygenase system. CH can either be oxidized by chloral hydrate dehydrogenase to trichloroacetic acid (TCA) or reduced by alcohol dehydrogenase to trichloroethanol (TCEtOH). The oxidation reaction requires NAD+, while the reduction reaction requires NADH. Since ethanol (EtOH) is known to alter the NAD+/NADH ratio in the hepatocyte, it was coadministered with TCE in an attempt to alter the metabolism of TCE. This would provide a means for predicting interactions of ethanol on the hepatotoxicity and carcinogenicity of TCE. Male Sprague-Dawley rats were administered oral doses of either 1.52, 4.56, or 22.8 mmol/kg TCE, with the treatment group receiving an additional 1.52, 4.56, or 22.8 mmol/kg EtOH, respectively. Blood and urine samples were collected over 72 h. The clearance of TCE appeared to be saturated at the 4.56 mmol/kg dose, as evidenced by prolonged residence times for TCE in the body. Consistent with this result, there was an attenuation of the increases in the levels of TCEtOH and TCA in blood. However, the time to peak concentration of these metabolites was delayed with increasing doses and their residence time in the body was prolonged. Therefore, the area under the curve (AUC) for TCEtOH and TCA continued to increase with the higher doses of TCE. Measurement of the net output of these metabolites in urine confirmed that, although metabolism was saturated, the net metabolic conversion of TCE increased. As predicted, EtOH decreased blood levels of TCA, but only at early times at the high dose. EtOH did increase the urinary TCEtOH/TCA ratio at all dose levels. These results are consistent with the hypothesis of a more reduced state in the hepatocyte caused by the generation of excessive reducing equivalents by EtOH metabolism. The metabolism of TCE is shifted toward reduction to TCEtOH, away from oxidation to TCA. However, the effect was prominent only at extremely high doses of TCE and EtOH.     

Extrahepatic organs metabolism of inhaled trichloroethylene

An extrahepatic circulation system for dogs was developed using a portal vein to right femoral vein bypass procedure. This system maintained nearly normal biochemical and physiological parameters, i.e. arterial blood pressure, heart rate, electrocardiogram, leukocyte and erythrocyte count, hematocrit, alkaline phosphatase, blood urea nitrogen, ammonia and creatinine, for 2 h. Thus, the system appears to be a valid technique for investigating extrahepatic metabolism. Dogs were exposed for 1 h to 500, 700 and 1500 ppm of trichloroethylene. Free-trichloroethanol, trichloroacetic acid and conjugated-trichloroethanol appeared in the blood and urine after 30 min of exposure. The amounts of metabolite formed by dogs with hepatic bypass were less than by similarly exposed dogs without hepatic bypasses, specifically 50-80%, 10% and 10-20% for free-trichloroethanol, trichloroacetic acid and conjugated-trichloroethanol, respectively. In addition, trichloroethylene exposure produced a smaller decrease in leukocyte counts in the hepatic bypass dogs than in the non-bypass dogs. This observation may indicate that the liver itself played some role in the elimination or increment of leukocyte counts in the blood.     

Enhancement of allyl alcohol hepatotoxicity by endotoxin requires extrahepatic factors.

Noninjurious doses of bacterial endotoxin (lipopolysaccharide; LPS) enhance allyl alcohol-induced liver damage in rats in a Kupffer cell (KC)-dependent fashion. To investigate the mechanism by which KCs contribute to liver injury in this model, isolated KCs and hepatocytes (HCs) were cocultured. Addition of LPS to the cocultured cells did not enhance allyl alcohol-induced cytotoxicity. In addition, recirculating perfusion of isolated livers from na?ve rats with LPS for 2 h did not significantly enhance allyl alcohol-induced toxicity as measured by release of alanine aminotransferase (ALT). These results suggest an extrahepatic factor is required for LPS potentiation of allyl alcohol hepatotoxicity. To examine whether the coagulation cascade contributes to injury in this model, rats were given either warfarin at 42 and 18 h before LPS, or heparin at 1 h before LPS, and were treated with allyl alcohol 2 h after LPS. Warfarin and heparin each significantly blocked the decrease in plasma fibrinogen levels and attenuated the increase in plasma ALT activity in rats treated with LPS and allyl alcohol. To assess the role of thrombin in this injury, isolated livers from rats pretreated with LPS were perfused with thrombin or vehicle and allyl alcohol. Though LPS pretreatment enhanced the toxicity of allyl alcohol compared with livers from na?ve rats, perfusion with thrombin did not increase sensitivity to allyl alcohol. In summary, LPS augments the hepatotoxicity of allyl alcohol through a mechanism involving extrahepatic factors, one of which may be a component of the coagulation cascade.     

Species differences in the metabolism of trichloroethylene to the carcinogenic metabolites trichloroacetate and dichloroacetate.

Differing rates and extent of trichloroethylene (TCE) metabolism have been implicated as being responsible for varying sensitivities of mice and rats to the hepatocarcinogenic effects of TCE. Recent data indicate that the induction of hepatic tumors in mice may be attributed to the metabolites trichloroacetate (TCA) and/or dichloroacetate (DCA). The present study was directed at determining whether mice and rats varied in (1) the peak blood concentrations, (2) the area under the blood concentration over time curves (AUC) for TCE and metabolites in blood, and (3) the net excretion of TCE to these metabolites in urine in the dose range used in the cancer bioassays of TCE, and to contrast the kinetic parameters observed for TCE-derived TCA and DCA with those obtained following direct administration of TCA and DCA. Blood and urine samples were collected over 72 hr from rats and mice after a single oral dose of TCE of 1.5 to 23 mmol/kg. The AUC values from the blood concentration with time profiles of TCE, TCA, and trichloroethanol (TCOH) were similar for Sprague-Dawley rats and B6C3F1 mice. Likewise, the percentages of initial TCE dose recovered as the urinary metabolites TCA and TCOH were comparable. Nevertheless, the peak blood concentrations of TCE, TCA, and TCOH observed in mice were much greater than those in rats, while the residence time of TCE and metabolites was prolonged in rats relative to that of mice. DCA was detected in the blood of mice but not in rats. The blood concentrations of DCA observed in mice given a carcinogenic dose of TCE (15 mmol/kg) were of the same magnitude as those observed with carcinogenic doses of DCA. In conclusion, the net metabolism of TCE to TCA and TCOH was similar in rats and mice. The initial rates of metabolism of TCE to TCA, however, were much higher in mice, especially as the TCE dose was increased, leading to greater concentrations of TCA and DCA in mice approximated those produced by carcinogenic doses of the chlorinated acetates makes it highly likely that both compounds play a role in the induction of hepatic tumors in mice by TCE.     

Morphological and biochemical analyses of trichloroethylene hepatotoxicity: differences in ethanol- and phenobarbital-pretreated rats

The histological and biochemical differences between ethanol- and phenobarbital (PB)-potentiated hepatotoxicity of trichloroethylene (TRI) in Wistar strain male rats were investigated. Both ethanol (2 g in daily liquid diet for 3 weeks) and PB (80 mg/kg/day for 4 days, ip) pretreatments enhanced TRI (inhalation exposures of 500 ppm for 8 hr, 2000 ppm for 2 or 8 hr, and 8000 ppm for 2 hr)-induced hepatic damage as judged by increases in plasma transaminase activities. Livers from PB-treated rats exposed to TRI displayed centrilobular necrosis, whereas livers from ethanol-treated rats exposed to TRI were characterized by ballooning degeneration mainly in midzonal areas. TRI exposure decreased the in vitro metabolism of TRI, high-Km benzene aromatic hydroxylase (BAH) activity, and cytochrome P450 content in livers of PB-treated rats with severe hepatic damage. In ethanol-treated rats, TRI exposure increased both the in vitro metabolism of TRI and the low-Km BAH activity but did not cause an apparent decrease in cytochrome P450 content even in animals with severe hepatic damage. These results suggest that TRI caused necrosis of centrilobular hepatocytes in PB-pretreated rats, which was accompanied by loss of xenobiotic metabolizing functions, whereas ballooning degeneration of hepatocytes mainly in midzonal areas occurred in ethanol-pretreated rats without loss of xenobiotic metabolizing functions.     

Cytochrome p450-dependent metabolism of trichloroethylene in rat kidney.

The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite consistently detected and was used as a measurement of P450-dependent metabolism of Tri. Pretreatment of rats with pyridine increased CH formation in both liver and kidney microsomes, whereas pretreatment of rats with clofibrate increased CH formation only in kidney microsomes. Pyridine increased CYP2E1 expression in both liver and kidney microsomes, whereas clofibrate had no effect on hepatic but increased renal CYP2E1 and CYP2C11 protein levels. These results suggest a role for CYP2E1 in both the hepatic and renal metabolism of Tri and a role for CYP2C11 in the renal metabolism of Tri. Studies with the general P450 inhibitor SKF-525A and the CYP2E1 competitive substrate chlorzoxazone provided additional support for the role of CYP2E1 in both tissues. CH formation was higher in PT cells than in DT cells and was time and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent. However, pretreatment of rats with either pyridine or clofibrate had no effect on CYP2E1 or CYP2C11 protein levels or on CH formation in isolated cells. These data show for the first time that Tri can be metabolized to at least one of its P450 metabolites in the kidneys and quantitate the effect of P450 induction on Tri metabolism in the rat kidney.     

维生素E和银杏叶提取物对3种氯代烯烃细胞毒性的拮抗作用

目的探讨维生素E和银杏叶提取物(ginkgo biloba extract，GbE)对三氯乙烯(trichloroethylene，TCE)、四氯乙烯(perchloroethylene，PCE)和二氯乙烯(diehloroethylene，DCE)所致人角质形成细胞(keratinocyte，Kc)细胞毒性的拮抗作用。方法利用中性红吸附(neutral red uptake，NRU)试验和乳酸脱氢酶(lactate dehydrogenase，LDH)释放试验分别测定细胞活力和细胞毒性，分析维生素E和GbE对3种氯代烯烃的细胞毒性拮抗作用。结果维生素E和GbE对3种氯代烯烃的细胞毒性具有明显的拮抗作用，在10～100mmol／L(mg／L)范围内呈明显的剂量．效应关系，当维生素E浓度达到50mmol／L，GbE浓度达到150mg／L时，细胞基本恢复为正常的状态。结论vE和GbE对3种氯代烯烃所致KC细胞毒性的拮抗作用可能与它们稳定细胞膜结构，减少细胞膜损伤有关。     

The metabolism of trichloroethylene and its metabolites in the perfused liver

The metabolism of trichloroethylene (TRI) and its metabolites, chloral hydrate (CH), trichloroethanol (free-TCE) and trichloroacetic acid (TCA), were examined in the isolated perfused rat liver, to clarify the role of the liver in the metabolism of TRI. TRI was rapidly converted to TCE and TCA by the perfused liver. TCA was produced from TRI about 2.5 times greater than was total-TCE. CH was metabolized to TCE and TCA immediately. TCA was also a dominant metabolite of CH over total-TCE. TCE(free type) was speedily conjugated by the liver. A portion of TCE was converted to TCA. Less than 10% of these metabolites produced by the liver were excreted into the bile. Most of them appeared in the perfusate.     

Role of metabolism in parathion-induced hepatotoxicity and immunotoxicity

The objective of this study was to investigate whether metabolic activation of parathion by cytochrome P-450s (CYPs) was responsible for pesticide-induced hepatotoxicity and immunotoxicity. Initially, to investigate parathion metabolism in vitro, the production of paraoxon and p-nitrophenol, major metabolites of parathion, was determined by high-performance liquid chromatography (HPLC). Subsequently, metabolic fate and CYP enzymes involved in the metabolism of parathion were partially monitored in rat liver microsomes in the presence of the NADPH-generating system. Among others, phenobarbital (PB)-induced microsomes produced the metabolites paraoxon and p-nitrophenol to the greatest extent, indicating the involvement of CYP 2B in parathion metabolism. When female BALB/c mice were treated orally with 1, 4, or 16 mg/kg of parathion in corn oil once, parathion suppressed the antibody response to sheep red blood cells. To further investigate a possible role of metabolic activation by CYP enzymes in parathion-induced toxicity, female BALB/c mice were pretreated intraperitoneally with 40 mg/kg PB for 3 d, followed by a single oral treatment with 16 mg/kg parathion. PB pretreatment produced a decrease in hepatic glutathione content and increases in hepatotoxic paramenters in parathion-treated mice with no changes in the antibody response. In addition, greater p-nitrophenol amounts were produced when mice were pretreated with PB, compared to treatment with parathion alone. These results indicate that parathion-induced hepatotoxicity might be differentiated from immunotoxicity in mice.     

Impaired mitochondrial oxidative energy metabolism following paracetamol-induced hepatotoxicity in the rat.

1. Effects of paracetamol treatment in vivo at subtoxic (375 mg kg-1 body weight) and toxic (750 mg kg-1 body weight) doses on energy metabolism in rat liver mitochondria were examined. 2. Paracetamol treatment resulted in a significant loss in body weights without affecting the liver protein contents. Toxic doses, however, resulted in 21% decrease in the yield of mitochondrial proteins. 3. Subtoxic doses of paracetamol did not, in general, affect the respiratory parameters in the liver mitochondria except in the case of succinate where both the state 3 respiration and the ADP-phosphorylation rates increased by 28%. 4. Toxic doses of paracetamol caused 25 to 47% decrease in the state 3 respiration rates depending on the substrate used. ADP/O ratios also decreased significantly with pyruvate + malate and succinate as the substrates. Consequently, ADP-phosphorylation was impaired significantly from 20 to 63%. 5. Subtoxic doses of paracetamol resulted in increased contents of cytochrome c + c1 while the toxic doses caused lowering of the cytochromes aa3 and b contents. 6. Glutamate and succinate dehydrogenase activities decreased in both the experimental groups while Mg2+-ATPase activity was impaired only after toxic dose-treatment. 7. The results show that toxic doses of paracetamol result in impaired energy coupling in the liver mitochondria. Effects of subtoxic doses were also demonstrable in terms of impaired dehydrogenases activities.     

The role of metabolism in chloroform hepatotoxicity

Since there is indirect evidence that a metabolite may be responsible for the hepatotoxicity of CCl₄, the possibility that chloroform may also act through a similar mechanism was investigated. Pretreatment with stimulators of drug metabolizing enzymes like phenobarbital, 3-methylcholanthrene or 3,4-benzopyrene increased the toxicity of chlorform in rats, as reflected by increased serum glutamic-pyruvic transaminase and a decrease in liver glucose-6-phosphatase activity. This enhancement of the toxicity of CHCl₃ was associated with an increase in ¹⁴CHCl₃ metabolism, as measured by pulmonary excretion of ¹⁴CO₂. An inhibitor of drug metabolizing enzymes, SKF 525-A, was found to decrease pulmonary excretion of ¹⁴CO₂. If these observations may be taken as indirect evidence that the hepatotoxic effect of CHCl₃ is due to a metabolite, other data do not seem to support such an hypothesis. No metabolite of CHCl₃ could be detected by gas-liquid chromatography; there was no quantitative correlation between the increase in toxicity and the increase in CHCl₃ metabolism. Finally, SKF 525-A did not decrease CHCl₃ hepatotoxicity. It is concluded that metabolism of CHCl₃ may be involved in the hepatotoxic effect of CHCl₃, but other factors may also play a role in determining this response.     

Role of metabolism in drug-induced idiosyncratic hepatotoxicity

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.