Cimetidine Protects Against Acetaminophen Hepatotoxicity in Rats
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1 GASTROENTEROLOGY 1981;81:152-6 Cimetidine Protects Against Acetaminophen Hepatotoxicity in Rats MACK C. MITCHELL, STEVEN SCHENKER, G.R. AVANT, and K.V. SPEEG, JR. Department of Medicine. Vanderbilt University. and Veterans Administration Medical Center. Nashville. Tennessee Acetaminophen hepatotoxicity is believed to result from the metabolic conversion of acetaminophen to a highly reactive intermediate by cytochrome P 45. Cimetidine has been shown to be a potent inhibitor of cytochrome P 45-mediated drug metabolism in humans and in laboratory animals, -both in vivo and in vitro. Therefore, this study was undertaken to examine the possible protective effects of cimetidine administration on acetaminophen-induced hepatic necrosis in rats. We observed a striking protection against acetaminophen hepatotoxicity in cimetidine-treated rats (12 mg/kg) up to 4 h after i.p. administration of 5 mg/kg of acetaminophen. Cimetidine-treated animals had less histologic damage when examined by light microscopy. and they had lower serum aminotransferases than those treated with acetaminophen alone. Furthermore. there was less functional hepatic impairment. e.g.. improved survival and improved ability to metabolie aminopyrine in vivo in rats receiving cimetidine compared with those receiving acetaminophen without cimetidine. Comparison of cjmetidine treatment with N-acetylcysteine treatment of acetaminophen overdose in rats showed cimetidine as effective as N acetylcysteine, even though the dose of cimetidine given was only isth that of N-acetylcysteine on a molar basis. Cimetidine also inhibited the covalent binding of [3H]acetaminophen to hepatic microsomes in vitro, both in the presence and absence of reduced glutathione. Cimetidine did not, however, Received June Accepted August Address requests for reprints to: K.V. Speeg. Jr. M.D.. Ph.D.. Division of Gastroenterology, Veterans Administration Medical Center, th Avenue South, Nashville. Tennessee This work was supported by the Veterans Administration and by National Institutes of Health Grant GM Dr. Mitchell is the recipient of a National Institutes of Health Individual Research Fellowship Award. The authors are indebted to Mr. Raymond Parker for his excellent technical assistance by the American Gastroenterological Association /81/ $2.5 increase total hepatic glutathione stores within 4 h of its i.p. administration. Thus, we have shown that cimetidine effectively reduces acetaminophen hepatotoxicity in rats. Although the exact mechanism of its protective action is unproven, it seems likely that cimetidine inhibits the formation of the reactive metabolite of acetaminophen both in vivo and in vitro. Overdoses of and accidental poisonings with acetaminophen are becoming more prevalent problems both in the United States and worldwide (1). Large doses of acetaminophen have been shown to cause severe hepatic necrosis both in laboratory animals and in humans. Toxicity is thought to be related to production of a highly reactive intermediate metabolite that results from oxidation of acetaminophen by cytochrome P 45 monooxygenases (2). This reactive metabolite is thought to bind to macromolecules within hepatocytes, and thus result in irreversible damage and subsequent cell death (3,4). The major pathway for elimination of acetaminophen is conjugation with glucuronic and sulfuric acid (5-7). With therapeutic doses of acetaminophen, only a small amount of this toxic intermediate is formed by cytochrome P 45-mediated oxidation, and this prduct is usually conjugated with glutathione, thereby rendering the compound nontoxic. However, after massive doses of acetaminophen, formation of the toxic intermediate exceeds the abilities of the liver and kidney to form glutathione conjugates, and binding to cellular macromolecules and subsequent necrosis result (3,8). Current treatment of acetaminophen overdose has consisted of administering agents that increase availability of glutathione, serve as substitutes for glutathione in forming conjugates with the toxic metabolite, or increase the elimination of acetaminophen by sulfation (9,1). In a recent review of the mechanism of acetaminophen toxicity, Gillette pointed out that both the rate of formation and the rate of
2 December 1981 CIMETIDINE AND ACETAMINOPHEN TOXICITY 153 elimination of the toxic metabolite are important in determining the degree of covalent binding and cell damage that may result (11). Few studies have been directed towards reducing the hepatotoxicity of acetaminophen by inhibiting the rate of formation of the toxic intermediate. Cimetidine has been shown to be a potent inhibitor of cytochrome P 45-mediated drug metabolism both in laboratory animals and in humans after the usual therapeutic doses (12-14). Furthermore, previous studies have demonstrated that cimetidine does not affect the rate of glucuronidation of drugs in humans (15) or in animals in vitro (Mitchell MC: unpublished observations). Therefore, administration of cimetidine should result in a reduction in the hepatotoxicity of acetaminophen after massive doses. Rats are relatively insensitive to the hepatotoxic effects of large doses of acetaminophen unless they are pretreated with inducers of microsomal oxidation such as phenobarbital or 3-methylcholanthrene (3-MC). Phenobarbital may also increase the rate of glucuronidation of acetaminophen in rats, whereas 3-MC pretreatment has no effect on hepatic glucuronidation (16). Such an increase in glucuronidation would tend to diminish the effects of increased oxidation because the nontoxic glucuronide would be formed in greater amounts. Therefore, we have studied the effects of cimetidine on the hepatotoxicity of acetaminophen after a single i.p. dose of acetaminophen in rats pretreated with 3-MC. Materials and Methods Pretreatment of Animals Male, 6-s-wk-old Fischer 344 rats (7-11 g; Harlan Industries, Indianapolis, Ind.), were injected with a single dose of 3-methylcholanthrene (Eastman Laboratory and Special Chemicals, Rochester, N.Y.) 2 mg/kg in corn oil. Animals were used 72 h after pretreatment with 3-MC after an overnight fast. Fasting was continued throughout the duration of each experiment, although the animals were allowed free access to water. Experimental Treatment of Animals Acetaminophen (Sigma Chemical Co., St. Louis, Mo.) was prepared as a supersaturated solution, 5 mg/ml in distilled water at 45 C, for injection. Cimetidine (Tagamet, Smith, Kline & French, Philadelphia, Pa.) was given as a solution containing 15 mg/ml. N-Acetylcysteine (Mucomyst, Meade-Johnson, Evansville, Ind.) was given as a 2% solution. Acetaminophen was given as a single i.p. dose of 5 mg/kg. Cimetidine was given in two i.p. doses (12 mglkg), which has previously been shown to inhibit cytochrome P 45-mediated drug metabolism in the rat in vivo (12). In one group of animals, cimetidine was given 1 h before administration of acetaminophen and again 6 h after acetaminophen. In another group, cimetidine was given 4 h after administration of acetaminophen and again 1 h after acetaminophen. N-Acetylcysteine was given in two i.p. doses (1. glkg)-which has previously been shown to protect against acetaminophen hepatotoxicity in mice (17)-beginning either 1 h before or 4 h after administration of acetaminophen, as described above for cimetidine. Survival. Survival was recorded 24 h after administration of acetaminophen. Surviving rats were killed by exsanguination from the abdominal aorta under light ether anesthesia. Blood was collected for determination of serum aminotransferase activities. Sections of the livers from these animals were fixed in 1% formalin and embedded in paraffin for histologic examination. Histologic Examination Coded histologic sections were examined under light microscopy by three "blinded" observers. The extent of necrosis was graded from to 4+ as follows: Histologically normal sections were graded o. Minimal centrilobular necrosis was graded 1 +; more extensive necrosis confined to centrilobular regions was graded 2 +; necrosis extending from central ones to portal triads was graded 3+; and massive necrosis of most of the liver was graded 4+ (Figure 1). Serum Aminotransferase Determinations Serum aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) were determined by the method of Reitman and Frankel with kits obtained from Sigma Chemical Company (is). Aminopyrine Metabolism The ability of surviving rats to metabolie aminopyrine was measured to determine the degree of impairment of one metabolic detoxifying function of the liver in animals after acetaminophen administration. [14C]Aminopyrine breath tests were performed as previously described (12) in different groups of animals, pretreated with 3-MC, and fasted overnight as described above. Total exhaled 14COZ was collected over 15-min intervals for 9 min. Results were expressed as the percentage of labeled [14C]aminopyrine (13 mcilmmol; AmershamlSearle, Chicago, Ill.) appearing in the breath as 14CO over time. Four groups of rats were studied: In one group, cimetidine alone was given as two doses of 12 mglkg 7 h apart. Two other groups of rats were treated either with acetaminophen (5 mglkg i.p.) alone or with acetaminophen combined with cimetidine pretreatment given according to the schedule described above. The fourth group received saline only. Breath tests were carried out in all animals surviving 24 h after administration of acetaminophen.
3 154 MITCHELL ET AL. GASTROENTEROLOGY Vol. 81, No.6.I.,.. i ",.,., _..' "'.\ ' (..-.{"::":' \,... " '".. - "-r"i.:.: \ Figure 1. Histologic damage after acetaminophen administration in 3-MC pretreated rats. A. Grade : no damage (x 1). B. Grade 1 +: early ballooning and eosinophilic degeneration of cytoplasm in centrilobular hepatocytes (x 1). C. Grade 2 +: similar, but more extensive damage than in B (x 1). D. Grade 3+ : extensive loss of centrilobular hepatocytes (x 2). E. Grade 4+: massive centrilobular and midonal hepatic necrosis with sparing of only periportal hepatocytes (x 1).
4 December 1981 CIMETIDINE AND ACETAMINOPHEN TOXICITY l <t 75 > > a:: ::::> (f) a:: I <t N 5 25 *.--- ** P<.5 ** p<.oooi r--- 14/32 16/22 2/2 9/18 ACETAMINOPHEN ONLY CIMETIDINE CIMETIDINE N-AC-CYS 4HRS POST I HR PRE 4 HRS POST 1/1 + N-AC-CYS I HR PRE Figure 2. Twenty-four-hour survival in rats treated with acetaminophen, acetaminophen plus cimetidine, or acetaminophen plus N-acetylcysteine (N-Ac-cys). 3 MC-pretreated rats were fasted for 18 hand given 5 mg/kg of acetaminophen intraperitoneally. Cimetidine (12 mglkg) pretreatment was given intraperitoneal Iy 1 h before and 6 h after acetaminophen. Cimetidine (12 mg/kg) posttreatment was given i.p. 4 and 1 h after acetaminophen. N-Acetylcysteine (1. gmlkg) was given i.p. 1 h before and 6 h after acetaminophen. N-acetylcysteine posttreatment was given 4 and 1 h after acetaminophen. Covalent Binding of eh]acetaminophen to Liver Microsomes Covalent binding of acetaminophen to liver microsomes was determined by a modification of the method of Potter et al in animals pretreated with 3-MC 72 h before death (4). Microsomes were prepared by differential centrifugation, washed with 1.15% KCI, and resuspended in 5 mm Tris-CI (ph 7.4) as previously described (19). Microsomes were then incubated for 3 min at 37 C with 1. /-LCi of [3Hlacetaminophen (9.3 Ci/mmole; New England Nuclear, Boston, Mass.) and varying amounts of unlabeled acetaminophen in the presence of 1. mm NADPH (P-L Biochemicals, Milwaukee, Wisc.). The reaction was stopped by the addition of cold 1% trichloroacetic acid (TeA). The resulting precipitate was washed once with 5. ml of cold TCA and twice with 1% ethanol, and was then solubilied in 1. ml of 1. N NaOH. The solubilied precipitate was then added to 1 ml of acidified aqueous counting scintillant (ACS) (Amershaml Searle) and counted by liquid scintillation spectrometry. Results are expressed as picomoles of acetaminophen covalently bound per milligram microsomal protein per minute. Nonspecific binding of [3H]acetaminophen was subtracted by using a ero incubation time control The effect of cimetidine on covalent binding of acetaminophen to liver microsomes was studied after addition of cimetidine (.2-2. mm, final concentration) to the incubation mixture. In addition, the inhibition of covalent binding of acetaminophen by 2. mm cimetidine was studied in the presence of varying concentrations of reduced glutathione. Effect of Cimetidine on Hepatic Glutathione Content Rats pretreated with 3-methylcholanthrene were fasted overnight as described above. Cimetidine (12 mg/ kg) was given as a single i.p. dose, and animals were killed at 1-h intervals. Total hepatic glutathione was determined according to the method of Tiete after homogeniing the liver sections in ice-cold 1% TCA/O.Ol N HCl (2). Statistics Student's t-test for unpaired samples was used to compare means between groups. A X2 2 x 2 contingency table was used to compare survival between groups. The minimum level of significance was considered to be p <.5 (two-tailed) unless otherwise specified. Results were expressed as the mean ± SEM unless otherwise specified. Results Survival Acetaminophen given as a single Lp. dose of 5 mg/kg resulted in a 56% mortality at 24 h in animals receiving no further treatment. In contrast, all animals pretreated with cimetidine according to the schedule described in Methods before receiving the same dose of acetaminophen survived 24 h (p <.1). Furthermore, the mortality was significantly reduced to 27%, less than one-half that of the untreated group ( p <.5), in those animals that were given cimetidine (12 mg/kg i.p.) four and 1 h after administration of acetaminophen. By comparison, treatment with N-acetylcysteine (1. g/kg Lp.) given 4 and 1 h after acetaminophen, did not reduce the mortality substantially, as 5% of these animals were dead at 24 h (p >.5). However, animals pretreated with N-acetylcysteine 1 h before administration of acetaminophen were all protected (p <.1). These results are shown in Figure 2. Serum Aminotransferases Serum aspartate aminotransferase (SGOT) and serum alanine aminotransferase (SGPT) activities were measured in all animals surviving 24 h after acetaminophen administration (Figure 3). Control
5 156 MITCHELL ET AL. GASTROENTEROLOGY Vol. 81. No.6 8 A 6 It p<.2 :> u. * ** p< (!) (f) * Figure 3. Serum aspartate aminotransferase (SGOT) activity (A) and serum alanine aminotransferase (SGPT) activity (B) in rats treated with acetaminophen. acetaminophen + cimetidine and acetaminophen + N-acetyicysteine (N-Ac-cys). The treatment groups are the same as in Figure 2. Results are shown as the mean ::t: SEM. (n = 2 for each group except N Ac-Cys pretreatment. in which n = 1.) 2 3 ACETAMINOPHEN ONLY CIMETIDINE CIMETIDINE N-AC-CYS N-AC-CYS 4HRS POST I HR PRE 4 HRS POST I HR PRE ** B (f).- 2 :> "-.-.. (!) 1 It p<.2 ** p<.oooi ACETAMINOPHEN *It ** ONLY CIMETIDINE CIMETIDINE N-AC-CYS N-AC-CYS 4 HRS POST I HR PRE 4 HRS POST I HR PRE animals pretreated with 3-MC had a mean SGOT of 121 ± 6 Sigma-Frankel (SF) units/ml and a mean SGPT of 31 ± 3 SF units/ml. In animals receiving acetaminophen only, there was a striking elevation of both serum transaminases with a mean of 734 ± 1278 for SGOT and 2919 ± 462 for SGPT. In animals pretreated with cimetidine 1 h before acetaminophen, however, the mean SGOT and SGPT levels were less elevated, reaching only 2% of the acetaminophen only values (p <.1). Furthermore, animals receiving cimetidine 4 and 1 h after acetaminophen had SGOT and SGPT elevations of approximately one-half those seen after acetamino- phen only (p <.2). Pretreatment with N-acetylcysteine 1 h before acetaminophen resulted in a modest elevation of both SGOT and SGPT -similar to those seen with cimetidine pretreatment (p <.1), and N-acetylcysteine given 4 and 1 h after acetaminophen also resulted in a modest elevation of SGOT and SGPT in survivors at 24 h (p <.2). Histologic Changes Animals receiving acetaminophen showed evidence of marked hepatic necrosis when examined by light microscopy. The histologic index score was
6 December 1981 CIMETIDINE AND ACETAMINOPHEN TOXICITY lj <l: (/) W <l: (/) w I- <l: w I- - U W 16..., 12 ::::i w 8 N u! T I ME (min) Figure 4. [14C]Aminopyrine breath tests in rats treated with saline (e). acetaminophen (). cimetidine (A). and cimetidine + acetaminophen (). One microcurie [14C]aminopyrine was given to 3-MC-pretreated rats 24 h after administration of saline. two doses of cimetidine (12 mglkg) given 7 h apart. acetaminophen (5 mglkg), or cimetidine (12 mg/kg) 1 h before and 6 h after acetaminophen (5 mg/kg). Results shown are expressed as the mean percentage of the injected dose of ["4C]aminopyrine eliminated in the breath over 9 min :t SEM (n '" 18 for e. O. A; n = 14 for ) ±.3. By comparison, cimetidine-pretreated rats showed significantly less necrosis with a score of.95 ±.27 (p <.1). All N-acetylcysteinepretreated animals had histologically normal livers (p <.1). Rats treated with cimetidine 4 and 1 h after acetaminophen had less hepatic necrosis than those receiving acetaminophen only (2.23 ±.32) as did those receiving N-acetylcysteine 4 and 1 h after acetaminophen (1.95 ±.46), although the results were not statistically significant. Aminopyrine Metabolism Control rats pretreated with 3-MC and given 1. j.tci of [14C]aminopyrine i.p. eliminated 22.6 ± 1.5% of the label as exhaled 14C 2 within 9 min (Figure 4). Animals given 2 doses of 12 mglkg of cimetidine alone, 7 h apart, eliminated a similar amount of [14C]aminopyrine (given 18 h after the last dose of cimetidine) as 14C 2 (25.5 ± 1.7%). Twentyfour hours after receiving acetaminophen, a striking reduction in the capacity to metabolie aminopyrine was observed in those animals that received acetaminophen only: only 11.5 ±.5% of the injected dose of p4c]aminopyrine appeared in the breath at 9 min (p <.1 compared with control). By contrast, those animals receiving acetaminophen that were pretreated with cimetidine eliminated ± 1.9% of the injected dose, which is similar to control values (p >.5 compared with control; p <.1 compared with acetaminophen only). Covalent Binding to Microsomes In Vitro Addition of [3H]acetaminophen to microsomes from 3-MC-pretreated rats resulted in covalent binding of 5.3 pmoles of acetaminophen/mg microsomal protein/min at a concentration of.1 mm acetaminophen. Addition of cimetidine to the incubation mixture resulted in dose-related inhibition of covalent binding of acetaminophen with concentrations of cimetidine between.2 and 2. mm (Figure 5). Addition of glutathione also resulted in a dose-dependent inhibition of covalent binding of acetaminophen. However, at any given concentration of glutathione, addition of 2. mm cimetidine resulted in further inhibition of covalent binding until background levels were achieved (Figure 6). Effect of Cimetidine on Hepatic Glutathione Content Total hepatic glutathione was measured in animals after a single i.p. dose of 12 mg/kg of cimetidine in an effort to determine the possible mechanism of protection observed in animals given cimetidine before and after acetaminophen. All animals were pretreated with 3-MC 72 h earlier and were fasted overnight as in other experiments. The W I.. 1 :;;: <l: I- 9 w u- <l: ± 8 i<l u l?_ Z 7 o co 6 I- Z w 5..J <l: > u T I I I I I I CIMETIDINE (mm) Figure 5. Inhibition of covalent binding of [3Hlacetaminophen to hepatic microsomes in vitro by cimetidine. Microsomes (2.75 mg/mll from 3-MC-pretreated rats were incubated with 1. /-LCi of [3Hlacetaminophen..1 mm unlabeled acetaminophen. and 1. mm NADPH for 3 min at 37 C. Cimetidine was added in final concentrations shown above.
7 158 MITCHELL ET AL. GASTROENTEROLOGY Vol. 81. No. 6 >. C1> 2 E c: <.!) is iii I f- Z W --1 «> 8 L, ,-' L..I ---'-I o I 1 1 GSH(;JM) Figure 6. Inhibition of covalent binding to hepatic microsomes in vitro by cimetidine in the presence and absence of reduced glutathione (GSH). Microsomes (1.6 mg/ml) from 3-MC-pretreated rats were incubated with 1. /LCi of [3HJacetaminophen..1 mm unlabeled acetaminophen. and 1. mm NADPH for 3 min at 37 C, Reduced glutathione was added to the incubation mixture in final concentrations shown above in the presence or absence of 2. mm cimetidine. control value for total hepatic glutathione in these animals was 952 ± 151 /Lg/g liver (mean ± SD). A single dose of 12 mglkg of cimetidine had no significant effect on total hepatic glutathione within 4 h of its administration (Figure 7). Therefore, it appears that cimetidine did not increase total intrahepatic glutathione stores during the period of study. The capacity of cimetidine to reduce dithiobisnitrobenoic acid (Ellman's reagent) was also measured in vitro in a system containing 1. mm NADPH and 1. unit of glutathione reductase. The maximal reducing capacity of cimetidine was approximately 1 x 1-5 that of reduced glutathione (GSH) in the same system, on a molar basis. Discussion In 1973, Mitchell et al. first pointed out that acetaminophen hepatotoxicity could be decreased by concomitant administration of cysteine which was thought to be a precursor of glutathione (4). These initial observations led to the development of an effective therapy for acetaminophen overdoses in humans, which involved administration of cysteamine (21,22). Other thiocompounds such as N acetylcysteine, methionine, dithiocarb, and, recently, propylthiouracil have also been shown to decrease acetaminophen hepatotoxicity (17,23-26). Although the definite toxic metabolite remains unidentified, several studies have suggested that N acetyl-p-benoquinoneimine may be the arylating intermediate that is formed during cytochrome P 45- mediated oxidation of acetaminophen (27,28). Thio- compounds such as those mentioned above are thought to reduce acetaminophen toxicity by decreasing the amount of the toxic metabolite that is covalently bound to hepatic proteins and other macromolecules, thus causing cell necrosis. However, other studies have shown an increase in the rate of elimination of acetaminophen from animals after administration of N-acetylcysteine, suggesting that a possible protective effect of this drug could occur by reducing the amount of acetaminophen available for conversion to the toxic product through increasing the formation of acetaminophen sulfate (1). Ascorbic acid has been demonstrated to reduce covalent binding of labeled acetaminophen to liver microsomes, presumably by reducing the oxidied product back to the parent compound (28). In humans, however, ascorbic acid competes with acetaminophen for conjugation to 3'-phosphoadenosine-5' phosphosulfate after therapeutic doses of acetaminophen, which results in delayed elimination of acetaminophen from plasma (29). Another proposed mechanism of action for the protective effect of thiocompounds such as a-mercaptoproprionylglycine is stabiliation of cellular constituents against the possible deleterious effects of covalent binding of the reactive metabolite (3). We have observed a striking protection from acet- Figure 15.,?: E c: w 6 1 I f- «f- :;) --1 <.!) u Q. W I --1 «f o f- 5 NS NS NS r r--- - f- r-i- - I- CONTROL 2 4 HOURS POST CIMETIDINE 7. The effects of cimetidine on total hepatic glutathione stores. 3-MC-pretreated rats were fasted 18 h and given cimetidine (12 mg/kg) or an equal volume of saline i.p. Animals were killed at times shown above. and the livers were removed. blotted. weighed. and homogenied in ice-cold 1% TCNO.1 N HCI with a Polytron homogenier. Total glutathione was determined by the method of Tiete (2). Results shown are expressed as micrograms of glutathione/gram wet liver. mean ± SEM (n =' 4 for each group).
8 December 1981 CIMETIDINE AND ACETAMINOPHEN TOXICITY 159 aminophen hepatotoxicity in rats treated with cimetidine up to 4 h after a single 5 mg/kg dose of acetaminophen. Less necrosis was seen in cimetidine-treated animals; as evidenced by less histologic damage and lower aminotransferases in survivors. In addition, there was less functional hepatic impairment as shown by improved survival and improved ability to metabolie aminopyrine in the cimetidinetreated groups. Cimetidine also reduced the amount of labeled acetaminophen covalently bound to liver micro somes in vitro. Cimetidine did not, however, appear to increase the total hepatic glutathione content in animals within 4 h of its administration. Previous studies have shown that cimetidine inhibits the metabolism of drugs that undergo oxidative biotransformation (phase I) in the liver (12-14). Cimetidine is a potent inhibitor of cytochrome P 45- mediated drug metabolism both in vivo and in vitro in hepatic microsomal preparations and homogenates. Patwardhan et al. have shown that cimetidine spares glucuronidation of some drugs in humans (15), and cimetidine also spares glucuronidation of paranitrophenol in rat liver microsomes (Mitchell MC: unpublished observations). It thus seems likely that the mechanism of protection against acetaminophen hepatotoxicity by cimetidine is related to the ability of cimetidine to selectively inhibit cytochrome P 45-mediated conversion of acetaminophen to its toxic metabolite(s) while allowing continued elimination of the parent drug to proceed via its major pathways of glucuronidation and sulfation. Other known inhibitors of cytochrome P 45-mediated drug metabolism have also been shown to be effective in reducing acetaminophen hepatotoxicity. Although piperonyl butoxide and cobaltous chloride have been shown to reduce binding of labeled acetaminophen to liver proteins, there was no decrease in acetaminophen induced mortality of mice pretreated with these agents (2,3). Metyrapone in a dose of 3 mg/kg has been shown to protect mice from acetaminophen hepatotoxicity (31). However, administration of metyrapone has the potentially undesirable side effect of reducing cortisol production (32). In conclusion, we have shown that cimetidine effectively reduces the hepatotoxicity of acetaminophen in rats. At this time, however, no studies of its efficacy in reducing acetaminophen hepatotoxicity in humans have been carried out. Thus, its use in treating acetaminophen hepatotoxicity in humans cannot be recommended at this time. Further studies to assess the inhibition of formation of the toxic metabolite that is later excreted as cysteine and mercapturic acid conjugates are needed, and are currently in progress in our laboratory. References 1. Black M. Acetaminophen hepatotoxicity. Gastroenterology 198;78: Mitchell JR, Jollow DJ, Potter WZ, et at. Acetaminopheninduced hepatic necrosis: Role of drug metabolism. J Pharmacol Exp Ther 1973;187: Jollow DJ, Mitchell JR, Potter WZ, et at. Acetaminopheninduced hepatic necrosis: role of covalent binding in vivo. J Pharmacol Exp Ther 1973;187: Potter WZ, Davis DC, Mitchell JR, et at. Acetaminopheninduced hepatic necrosis: cytochrome P-45-mediated covalent binding in vitro. J Pharmacol Exp Ther 1973;187: Brodie BB, Axelrod J. The estimation of acetanilide and its metabolic products, aniline, N-acetyl-p-aminophenol, and p amino phenol (free and total conjugated) in biological fluids and tissues. J Pharmacol Exp Ther 1948;94: Davis M, Simmons CJ, Harrison NG, Williams R. Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage. Q J Med 1976; 178: Howie D, Adriaenssens PI, Prescott LF. Paracetamol metabolism following overdosage: application of high performance liquid chromatography. J Pharm Pharmacol1977;18: Mitchell JR, Jollow DJ, Potter WZ, et at. Acetaminopheninduced hepatic necrosis: protective role of glutathione. J Pharmacol Exp Ther 1973;187: Slattery JT, Levy G. Reduction of acetaminophen toxicity by sodium sulfate in mice. Res Commun Chern Pathol Pharmacol 1977;18: Galinsky RE, Levy G. Effect of N-acetylcysteine on the pharmacokinetics of acetaminophen in rats. Life Sci 1979;5: Gillette JR. An integrated approach to the study of chemically reactive metabolites of acetaminophen. Arch Intern Med 1981;141: Desmond PV, Patwardhan R, Parker R, et at. Effect of cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffeine. Life Sci 198;26: Desmond PV, Patwardhan RV, Schenker S, Speeg KV. Cimetidine impairs the elimination of chlordiaepoxide (Librium) in man. Ann Intern Med 198;93: Pelkonen, Puurunen P. The effect of cimetidine on in vitro and in vivo drug metabolism in the rat. Biochem Pharmacol 198;29: Patwardhan RV, Yarborough GW, Desmond PV, et at. Cimetidine spares the glucuronidation of loraepam and oxaepam. Gastroenterology 198;79: Pessayre D, Wands cheer J-C, Colbert B, et at. Additive effects of inducers and fasting on acetaminophen hepatotoxicity. Biochem Pharmacol 198;29: Piperno E, Bressenbruee DA. Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 1976; 2: Reitman S, Frankel S. A colorimetric method for the determination of serum glutamine oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957;28: Franklin MR, Estabrook RW. On the inhibitory action of mersalyl on microsomal drug oxidation: a rigid organiation of the electron transport chain. Arch Biochem Biophys 1971; 143: Tiete F. Enymic method for quantitative determination of nanogram amounts of total and oxidied glutathione. Anal Biochem 1969;27: Prescott LF, Newton RW, Swains on CP, et at. Successful
9 16 MITCHELL ET AL. GASTROENTEROLOGY Vol. 81. No. 6 treatment of severe paracetamol (acetaminophen) overdose. Lancet 1976;2: Mitchell JR. Thorgeirsson SS. Potter WZ. et al. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. J Pharmacol Exp Thet 1974; 16: Prescott LF. Park J, Ballantyne A. et al. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 1977;2: Crome P. Vale JR. Volans GN. et al. Oral methionine in the treatment of severe paracetamol (acetaminophen) overdose. Lancet 1976;2: Strubelt O. Siegers C-P. Schutt A. The curative effects of cysteamine. cysteine and dithiocarb in experimental paracetamol poisoning. Arch Toxicol 1974;33: Yamada T. Ludwig S. Kuhlenkamp J, Kaplowit N. Direct protection against acetaminophen hepatotoxicity by propylthiouracil. J Clin Invest 1981;67: Calder IC. Creek MJ. Williams PJ. N-Hydroxyphenacetin as a precursor of 3-substituted 4-hydroxyacetanilide metabolites of phenacetin. Chern Bioi Interact 1974;8: Corcoran GB. Mitchell JR. Vaishnav YN. Horning EC. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate. N-acetyl-p-benoquinoneimine. Mol Pharmacol 198;18: Houston JB. Levy G. Drug biotransformation interactions in man. VI. Acetaminophen and ascorbic acid. J Pharm Sci 1976;65: Labadarios D. Davis M. Portmann B. Williams R. Paracetamolinduced hepatic necrosis in the mouse: relationship between covalent binding. hepatic glutathione depletion and the protective effect of a-mercaptoproprionylglycine. Biochem Pharmacol 1977;26: Goldstein M. Nelson EB. Metyrapone as a treatment for acetaminophen (paracetamol) toxicity in mice. Res Commun Chern Pathol PharmacoI1979;23: Temple TE. Liddle GW. Inhibitors of adrenal steroid biosynthesis. Ann Rev Pharmacol ToxicoI197;1:
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