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Induction of Hepatic CYP2E1 by a Subtoxic Dose of Acetaminophen in Rats: Increase in Dichloromethane Metabolism and Carboxyhemoglobin Elevation

College of Pharmacy (S.N.K., J.Y.S., D.W.J., M.Y.L., Y.S.J., Y.C.K.) and Research Institute of Pharmaceutical Sciences, College of Pharmacy (Y.C.K.), Seoul National University, Shinrim-Dong, Kwanak-Ku, Seoul, Korea

(Received March 2, 2007; Accepted July 3, 2007)

	Abstract

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Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.

Dichloromethane (DCM, CH₂Cl₂) is widely used in industry as a degreaser, as a solvent, as an extraction medium, and also as an important constituent of paint removers. Unlike its chemical congeners, such as carbon tetrachloride and chloroform, that are potent hepatotoxins, the liver toxicity of this substance is negligible (Nitschke et al., 1988). Instead, DCM is metabolically converted to carbon monoxide (CO) by CYP2E1 (Guengerich et al., 1991; Kim and Kim, 1996; Wirkner et al., 1997), leading to elevation of blood carboxyhemoglobin (COHb) levels. Accordingly hypoxia due to a decrease in O₂-carrying capacity constitutes a major toxicological problem associated with DCM exposure (Horowitz, 1986; Mahmud and Kales, 1999).

Although many studies have described the toxic consequences resulting from an excessively large dose of APAP, its potential adverse effects at a lower or therapeutic dose have hardly been explored. Considering the wide use of APAP in human, a better understanding of its effects at such a dose, presumed to be clinically nontoxic, seems to be relevant. In this study we investigated the effects of treating rats with a subtoxic dose of APAP on the metabolic disposition of DCM and COHb elevation. These two substances share common properties in that their toxic metabolites are generated via enzyme reactions mediated mostly by CYP2E1. Therefore, examination of the interaction between the two substances would provide valuable information regarding the effects of APAP administration on the metabolic fate and resulting consequences of various substances metabolically converted by the identical enzyme system.

	Materials and Methods

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Animals and Treatments. Female Sprague-Dawley rats (Dae-Han Laboratory Animal, Seoul, Korea) were acclimated in temperature (22 ± 2°C)- and humidity (55 ± 5%)-controlled rooms with a 12-h light/dark cycle for at least 3 weeks before use. The use of rats was in compliance with the guidelines established by the Animal Care Committee of this institute. A regular laboratory rat diet (Purina-Korea, Seoul, Korea) and tap water were allowed ad libitum until sacrifice. Rats, 10 to 14 weeks old and weighing 190 to 230 g, were treated i.p. with APAP (500 mg/kg) dissolved in 10% Tween 80. The volume of injection was 15 ml/kg. After 18 h DCM (3 mmol/kg), mixed with corn oil, was administered to rats i.p. The volume of injection was 2 ml/kg. Control animals were treated with an identical volume of each vehicle.

For the experiments determining blood COHb and DCM concentrations, a jugular vein was catheterized with silicon tubing (Dow Corning, Midland, MI) under ether anesthesia. The cannula was exteriorized to the dorsal side of neck and secured with a mounting post, which allowed attachment of an extensor for blood sampling. After surgery rats were housed individually in plastic metabolic cages (Myungjin, Seoul, Korea) and allowed to recover for 48 h. Every 10 to 15 h until the onset of experiment, the cannula was flushed with a heparin solution (20 units/ml physiological saline) to prevent blood clotting.

Assessment of Hepatotoxicity. Hepatotoxicity of APAP was estimated by elevation of serum enzyme activities. Eighteen hours after the treatment blood was sampled by cardiac puncture from each rat under light ether anesthesia. Serum sorbitol dehydrogenase (SDH) activity was determined spectrophotometrically according to the method described by Gerlach (1983). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum were determined using the method of Reitman and Frankel (1957).

Measurement of COHb and DCM Levels in Blood. Blood samples were obtained directly from the catheter inserted into a jugular vein. The COHb concentration in blood was determined using the method of Rodkey et al. (1979). In short, blood sample was diluted approximately 1500-fold with 0.01 M Tris solution containing sodium dithionite to prevent dissociation of COHb by oxygen. Absorbance measurements were made at 420 and 432 nm, the fraction of the total hemoglobin present as COHb was calculated from these measurements, and the molar absorptivities of hemoglobin and COHb were determined in this laboratory.

The DCM levels in blood were determined using a modification of the method reported previously (Kim and Carlson, 1986). Each 100-µl blood sample in a sealed vial stood at room temperature for 60 min. An aliquot (100 µl) of head-space vapor was sampled and injected into a gas chromatograph equipped with a flame ionization detector. A 2-m stainless steel column packed with 4% OV-101 and 6% OV-210 (Supelco, Bellefonte, PA) was used. Nitrogen was the carrier gas (30 ml/min), and air (300 ml/min) and hydrogen (30 ml/min) were used in the flame ionization detector. The column was set at 70°C, the detector at 150°C, and the injector at 130°C.

Measurement of Hepatic Glutathione Contents and Glutathione S-Transferase Activity. Hepatic total GSH contents were determined using an enzymatic recycling method of Griffith (1980). Whole liver was homogenized in ice-cold 1 M perchloric acid with 2 mM EDTA followed by centrifugation. An aliquot of the supernatant was mixed with 0.3 mM NADPH and 6 mM 5,5'-dithio-bis(2-nitrobenzoic acid). After addition of GSH reductase, the absorbance was monitored at 412 nm. Both DCM and 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP) are known to be substrates for the Theta class GST (Meyer et al., 1991). Therefore, cytosolic GST activity was measured using ENPP as a substrate according to the method of Habig et al. (1974).

Measurement of Microsomal Enzyme Activities. Whole liver was homogenized in an ice-cold buffer of 0.154 M KCl-50 mM Tris-HCl (pH 7.4) with 1 mM EDTA. Homogenate was centrifuged at 10,000g for 20 min, and the supernatant was further centrifuged at 104,000g for 60 min. The microsomal pellet was suspended in the homogenizing buffer followed by recentrifugation at 104,000g for 60 min. Protein contents were measured using the method of Lowry et al. (1951). The concentration of cytochrome P450 was estimated from the CO difference spectrum (Omura and Sato, 1964). The activity of NADPH-dependent P450 reductase was determined by using cytochrome c as a substrate (Phillips and Langdon, 1962). p-Nitrophenol hydroxylase activity was determined by measuring the formation of p-nitrocatechol (Koop, 1986). For measurement of chlorzoxazone 6-hydroxylase activity, reaction conditions identical to those described by Koop et al. (1997) were used. Quantification of 6-hydroxychlorzoxazone was conducted using a high-performance liquid chromatography method (Baek et al., 2006). p-Nitroanisole O-demethylase was determined using the method of Shigematsu et al. (1976). The production of formaldehyde was quantified for measurement of aminopyrine N-demethylase activity (Nash, 1953).

Western Blot Analysis. The microsomal suspension (10 µg of protein/lane) was loaded, separated by SDS-polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA) by electroblotting. The membranes were blocked in 5% nonfat dry milk in PBS-T (0.05% Tween 20 in PBS). The blots were incubated overnight with antibodies diluted in 5% bovine serum albumin in PBS-T at 4°C followed by incubation with secondary antibodies conjugated to horseradish peroxidase (diluted in 5% milk powder in PBS-T) for 3 h at room temperature. Rabbit polyclonal antibodies against human CYP2E1 and 3A4 (Detroit R&D, Detroit, MI) were used as probes. Proteins were detected by enhanced chemiluminescence on Kodak X-OMAT film (Sigma-Aldrich, St. Louis, MO) and scanning densitometry was performed with a microcomputer imaging device (model M1, Imaging Research, St. Catharines, ON, Canada).

Data Analysis. All results expressed as the mean ± S.E. were analyzed by a two-tailed Student's t test. The acceptable level of significance was established at p < 0.05 except when otherwise indicated. The half-life of DCM was derived from a semilogarithmic plot of blood DCM concentrations versus time using the method of least squares.

	Results

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Elevation of Serum Enzyme Activities by APAP Treatment. Serum AST, ALT, and SDH activities were determined in female rats treated with APAP at various doses (250-1000 mg/kg) (Table 1). At 18 h after the treatment serum enzyme activities were not elevated by an APAP dose of up to 500 mg/kg. Starting from the APAP dose of 750 mg/kg, the enzyme activities were increased, although the difference from control was not statistically significant until the dose reached 1000 mg/kg. In this study the maximal dose of APAP that did not influence the serum parameters in rats under normal feeding was determined to be 500 mg/kg. Therefore, all the subsequent experiments were conducted with this dose level.

COHb Elevation and Disappearance of DCM from Blood. In rats treated with a dose of DCM (3 mmol/kg i.p.), blood COHb levels were elevated rapidly, reaching a peak of 11% at 3 h after the treatment (Fig. 1). A dose of APAP 18 h before the DCM challenge enhanced the increase in COHb levels significantly. Elevation of COHb levels seemed to be more rapid, and the peak was higher in rats pretreated with APAP compared with that in rats treated with DCM only. The COHb levels of both groups returned to near-normal values in 6 h.

View larger version (11K): [in this window] [in a new window]   FIG. 1. Effect of APAP pretreatment on blood COHb elevation by DCM. Rats were treated with APAP (500 mg/kg i.p.) 18 h before DCM (3 mmol/kg i.p.). Each value represents the mean ± S.E. for six rats. * and **, significantly different from rats treated with DCM only (Student's t test, p < 0.05 and 0.01, respectively).

View larger version (11K): [in this window] [in a new window]   FIG. 2. Effect of APAP pretreatment on blood DCM levels. Rats were treated with APAP (500 mg/kg i.p.) 18 h before DCM (3 mmol/kg i.p.). Each value represents the mean of three rats. Standard error bars were omitted for the sake of clarity. * and **, significantly different from rats treated with DCM only (Student's t test, p < 0.05 and 0.01, respectively). The half-life of DCM obtained from the elimination curve was 40.9 ± 4.0 min for control rats and 33.6 ± 1.2 min for APAP-pretreated rats (Student's t test, p = 0.15).

Alterations in Metabolizing Enzyme System. Rats were treated with a dose of APAP (500 mg/kg i.p.) and sacrificed 18 h later to determine the hepatic metabolizing enzyme activities at the time point when DCM was administered (Table 2). The total cytochrome P450 contents were not changed by APAP treatment, but chlorzoxazone 6-hydroxylase, p-nitrophenol hydroxylase, and p-nitroanisole O-demethylase activities as well as NADPH-dependent P450 reductase activity were all increased in microsomes of rats treated with APAP. A small, but significant, increase in aminopyrine N-demethylase activity was also demonstrated. Hepatic GSH contents were not altered by a prior dose of APAP. There was no difference in the activity of GST measured with ENPP as a substrate between control and APAP-treated rats.

The expression of CYP2E1 and 3A proteins was determined in livers of rats that had been treated with APAP 18 h earlier (Fig. 3). Western blot analysis showed results comparable with those obtained from measurements of the hepatic microsomal metabolizing enzyme activities. An 18 h prior dose of APAP induced the expression of CYP2E1 protein in liver by 65%. CYP3A proteins were also increased significantly.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Expression of CYP2E1 and CYP3A4 in livers of rats treated with APAP. Rats were sacrificed 18 h after treatment with APAP (500 mg/kg i.p.) () or with the vehicle only (). Bands resolved by Western blotting were quantified densitometrically for comparison. Each value represents the mean ± S.E. for six rats. ** and ***, significantly different from rats treated with the vehicle only (Student's t test, p < 0.01 and 0.001, respectively).

	Discussion

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Pretreatment of rats with a subtoxic dose of APAP significantly increased the COHb elevation resulting from a DCM challenge in this study. The blood DCM levels were reduced, and its disappearance from blood also seemed to be more rapid in rats pretreated with APAP. The results indicate that the metabolic elimination of DCM and its conversion to CO are enhanced by pretreatment with an APAP dose incapable of elevating the serum enzyme activities.

Two major pathways are involved in the metabolic disposition of DCM: a microsomal oxidation process and a GSH-dependent cytosolic pathway. The microsomal reaction involves oxidative dechlorination of this solvent, resulting in production of CO and CO₂ via proposed intermediates chloromethanol and formyl chloride (Kubic and Anders, 1978). CYP2E1 was shown to be the major subtype of the cytochrome P450 family responsible for the metabolic conversion of DCM to CO (Guengerich et al., 1991). This pathway has a high affinity for DCM with limited capacity (McKenna et al., 1982). The alternative metabolic pathway of DCM is a reaction with GSH mediated by GSTs, especially the Theta class GST, which produces CO₂ via S-chloromethyl-GSH (GSCH₂Cl) and formaldehyde (Blocki et al., 1994; Mainwaring et al., 1996). This metabolic reaction shows no indication of saturation, suggesting that the cytosolic pathway is low-affinity, high-capacity compared with the P450-dependent reaction (Gargas et al., 1986). Therefore, the elevation of blood COHb resulting from a moderate dose of DCM is directly related to CYP2E1 activity in liver (Kim and Carlson, 1986; Kim and Kim, 1996).

In this study chlorzoxazone 6-hydroxylase, p-nitrophenol hydroxylase, and p-nitroanisole demethylase activities were all induced significantly in liver microsomes derived from animals treated with APAP 18 h earlier. p-Nitrophenol and chlorzoxazone are generally considered to be a selective substrate for CYP2E1 (Koop, 1986; Peter et al., 1990), although it has been suggested that CYP3A also makes a considerable contribution to hydroxylation of p-nitrophenol (Zerilli et al., 1997). Both CYP2E1 and 1A2 are involved in p-nitroanisole demethylase activity (Jones et al., 1997). The induction of chlorzoxazone 6-hydroxylase, p-nitrophenol hydroxylase, and p-nitroanisole demethylase activities (Table 2) is well correlated to the increase in CYP2E1 protein measured by Western blot analysis (Fig. 3). The results indicate that the increase in COHb elevation and DCM elimination in APAP-pretreated rats is associated with the induction of hepatic CYP2E1. Multiple forms of P450 isozyme including 2B1 and 3As are known to be involved in N-demethylation of aminopyrine (Imaoka et al., 1988). Therefore, the induction of aminopyrine N-demethylase activity was attributed to the increased expression of CYP3A enzymes.

In the cytosolic pathway that converts DCM into CO₂ via formaldehyde, GSH is required for formation of an intermediate, S-chloromethyl-GSH, but this tripeptide is regenerated and not consumed in the metabolic reaction (Ahmed and Anders, 1978). But previous studies conducted in this laboratory and also by others showed that treatment with a GSH-depleting agent, such as 2,3-epoxypropane, buthionine sulfoximine, and phorone, increased the COHb elevation and DCM elimination (Gargas et al., 1986; Oh et al., 2002), indicating that the availability of GSH may affect the metabolism of DCM via the microsomal P450-dependent reactions. The Theta class GST is known to play a major role in the metabolism of DCM via the GSH-dependent cytosolic pathway (Blocki et al., 1994; Mainwaring et al., 1996). In this study neither hepatic GSH contents nor the Theta class GST activity was influenced by the dose of APAP used, excluding a possibility that the increment in COHb elevation and DCM metabolism might be associated with a change in the GSH-dependent metabolic reaction.

It has been well established that the formation of a reactive metabolite of APAP by CYP activities is the critical event initiating various sequential cellular responses, ultimately leading to liver and kidney injuries. Because of the obvious role of P450 activities in APAP-mediated toxicity, many studies have been directed to identification of exogenous and endogenous factors that may modulate the enzyme activities and thereby alter the toxicological consequences resulting from an excessive dose of this drug. Because P450 activities are decreased by APAP at such a dose or level (Aikawa et al., 1977; Snawder et al., 1994; Shayiq et al., 1999), it is generally suspected that this drug would decrease the metabolism and activation of other toxic substances catalyzed by the same enzyme activities. However, the present results indicate that APAP, at a dose not capable of affecting the serum hepatotoxic parameters, may induce the CYP enzymes and metabolism of xenobiotics significantly. Induction of P450 enzymes by a subtoxic dose of APAP shown in this study was unexpected and seemed paradoxical. Extensive literature survey reveals that this issue has hardly been raised before. It was shown that the toxicity of several hepatotoxicants in rats was potentiated by a nontoxic dose of APAP (Wright and Moore, 1991). The authors suggested that this drug rendered hepatocytes susceptible to toxic insults via unknown mechanism(s). Plewka et al. (2000) demonstrated that treatment of rats with a low dose of APAP increased the total P450 contents, but expression of CYP2E1 and 1A2 appeared to be unaltered or reduced slightly in that study. The authors attributed the induction of total CYP to the need of liver cells to maintain the optimal P450-dependent monooxygenase system in a critical situation. Meanwhile a low concentration of APAP was shown to increase CYP3A4 contents and activity in transfected HepG2 cell line (Feierman et al., 2002). Its significance in whole animals was not assessed. Therefore, the present study is the first report demonstrating that a subtoxic dose of APAP to rats may induce the hepatic P450 enzymes and the metabolic reaction of a xenobiotic catalyzed by the P450 activities.

In conclusion, the present study indicates that APAP, at a dose not affecting the serum hepatotoxic parameters, may induce the hepatic CYP2E1 and 3A contents and the metabolic activities involved in the activation of this drug. It is also shown that the altered CYP2E1 contents may actually influence the metabolism and the resulting toxicity of a xenobiotic that is a substrate for the enzyme. The induction of hepatic CYP2E1 might result in potentiation of the toxicities of various chemicals which are converted to toxic metabolites by this enzyme, including numerous drugs, industrial and environmental chemicals, and natural substances. Considering the wide use of APAP as an analgesic-antipyretic, it is suggested that a greater concern should be expressed regarding the effects of acute or repeated dosing of this drug even at a therapeutic level, especially in combination with other medications. Further studies need to be undertaken to define the underlying mechanism and the extent of induction of the hepatic P450 enzymes by APAP.

	Footnotes

 
doi:10.1124/dmd.107.015545.

ABBREVIATIONS: APAP, acetaminophen; P450, cytochrome P450; DCM, dichloromethane, CH₂Cl₂; GSH, glutathione; CO, carbon monoxide; COHb, carboxyhemoglobin; SDH, sorbitol dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ENPP, 1,2-epoxy-3-(p-nitrophenoxy)-propane; GST, glutathione S-transferase; PBS, phosphate-buffered saline.

Address correspondence to: Dr. Young C. Kim, Professor of Toxicology, College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul, Korea. E-mail: youckim{at}snu.ac.kr

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