ࡱ> %` bjbjNN  ,,^)~~~~AAANCCdTDD^DDD[N[N[Nccccccc$#ghidu[NgM[N[N[Nd~~DDwdgagaga[N2~DDcga[NcgagaV?bhfcDD PA\JNc c\d0dZc _j^2_jfc_jfc,ga[N[N[Ndd a^[N[N[Nd[N[N[N[N&AA~~~~~~ Ketoconazole inhibits acetaminophen-induced hepatotoxicity in mice Filip ulo, Marija Reni, Domagoj Sabolovi*, Marko Radoa, Ante Bili and Vjekoslav Jagi! Objective: To investigate the effect of ketoconazole on acetaminophen (AAP)-induced hepatotoxicity in mice. Materials and methods: Mice were given AAP intragastrically (300 mg/kg) and treated with ketoconazole (100mg/kg intraperitoneally) or saline either 30 min before or 2-3 h after AAP administration. Mortality was recorded for 48 h, during which all mice given saline either died or recovered fully. Serum alanine and aspartate transaminase levels were determined 24 h after administration of AAP. Prostaglandin E2, thromboxane A2 and leukotriene C4 production was determined 6h after AAP administration in the supernatants from the short-term culture of liver fragments by radioimmunoassay. Results: Ketoconazole significantly decreased mortality and transaminase levels when given to mice either 30 min before or 2h after AAP. Liver fragments from mice with AAP hepatitis produced greater quantities of prostaglandin E2, thromboxane A2 and leukotriene C4 than fragments from normal liver. Pretreatment of mice with ketoconazole or its addition to liver fragments ex vivo further increased the production of prostaglandin E2 and reduced the production of thromboxane A2. The effect of ketoconazole on leukotriene C4 synthesis was different in vivo (synthesis stimulation) from in vitro (synthesis inhibition). Conclusion: The protective effect of ketoconazole in AAP hepatitis is most probably mediated by modulation of eicosanoid synthesis by liver cells. European Journal of Gastroenterology & Hepatology 1995, 7:757-762 Keywords: ketoconazole, acetaminophen, hepatitis, prostaglandins, leukotriene C4 Introduction Although primarily used as an antifungal agent, ketoconazole (KCZ) has multiple metabolic effects that may be exploited clinically. It inhibits steroid synthesis [1,2] and reduces degradation of cyclosporine by the liver, raising the blood level of this immunosuppressive agent [3]. These effects of KCZ are believed to result from its inhibition of liver cytochrome P-450 mixed oxidase function enzymes [4]. According to some reports, KCZ also interferes with metabolism of arachidonic acid, acting as a specific inhibitor of 5-lipoxygenase in rat peritoneal leukocytes [5]. This effect can explain its bronchodilatatory action in vivo [5] as well as its suppressive effect on the synthesis of tumour necrosis factor in vitro [6]. However, it seems that KCZ also influences the metabolism of cyclooxygenase products. The drug has been shown to inhibit the synthesis of thromboxane [7] while concomitantly stimulating the synthesis of prostaglandins PGE2 and PGD2 [7] in several human and guinea pig cell systems. At least two of these actions of KCZ have prompted us to investigate its effect on acetaminophen (AAP)-induced hepatitis in mice. First, it is believed that cytochrome P-450-dependent enzymes convert AAP in the liver into its active (hepatotoxic) metabolite [8], and that this process might be influenced by KCZ. Second, prostaglandins PGE2 [9] and PGI2 [10] as well as inhibitors of thromboxane synthesis [10] have a From the Department of Physiology and Immunology, School of Medicine, Zagreb, Croatia, *INSERM Unit 313, Groupe Pitie-Salpetriere, Paris, France, the Departments of +|nternal Medicine, and ^Clinical and Laboratory Diagnosis, Sveti Duh Hospital, Zagreb, Croatia. Requests for reprints to Dr F. Culo, Department of Physiology and Immunology, School of Medicine, Salata 3, 41000 Zagreb, Croatia. Date received: 28 November 1994; revised: 27 January 1995; accepted: 2 February 1995. Rapid Science Publishers ISSN 0954-691X 757 hepatoprotective effect, which closely parallels the effects of KCZ in some in vitro systems [7]. Finally, KCZ has been reported to inhibit the synthesis of 5-lipoxygenase products [5], the effect of which on hepatic injury is largely unknown. The data that we present here show a beneficial effect of KCZ on AAP-induced liver injury, which is probably related to its inhibitory effect on thromboxane synthesis. Materials and methods Animals CBA/H Zgr inbred mice were raised in an animal colony unit. Mice of both sexes aged 1216 weeks, weighing 20-25 g were used in the experiments. They were kept under standard laboratory conditions, fed with commercially available murine food pellets (K-l; Faculty of Biotechnology, Domzale, Slovenia) and given water ad libitum. Chemicals Pure AAP was a kind gift from the Krka pharmaceutical company (Novo Mesto, Slovenia). KCZ was kindly provided by the Belupo pharmaceutical company (Koprivnica, Croatia). D(+)-Galactosamine hydrochloride (DGalN) and lipopolysaccharide (LPS) from Salmonella enteritidis were purchased from Sigma (St Louis, Missouri, USA). AAP was dissolved in heated phosphate-buffered saline (PBS) to which 12 drops of Tween 80 were added, and 0.5 ml of the resulting suspension was administered intragastrically. KCZ was dissolved in the same way as AAP. The appropriate doses were generally given intraperitoneally in a volume of 0.2 ml, although in some experiments the drug was given orally. Control animals were given 0.2 ml pyrogen-free saline at the same time. DGalN and LPS were dissolved in sterile pyrogen-free saline and injected intraperitoneally as above. Induction of hepatitis with acetaminophen The procedure of Guarner et al. [10] was followed, with slight modifications. To induce hepatic drug-metabolizing enzymes, mice were given phenobarbitone-sodium (Kemika, Zagreb, Croatia) in their drinking water for 7 days (0.3 g/1). Thereafter, mice were fasted overnight and AAP was given intragastrically, via a stomach tube, in a volume of 0.5 ml. Animals were allowed food 4h later. In all experiments, a dose of 300 mg/kg AAP, which produced a mortality of 7179% in control mice, was administered. Induction of hepatitis with DGalN and LPS Mice were given an intraperitoneal injection of 650 mg/kg DGalN in a volume of 0.2 ml. One hour later, they received 0.01 mg/kg (0.2 Ug per mouse) intraperitoneal LPS. Plasma transaminase concentrations Transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] concentrations were measured 24 h after the administration of AAP. Plasma samples were obtained by a procedure in which haemolysis was undetectable. Mice were given 250 units intraperitoneal heparin 15min before bleeding. Blood was obtained by puncturing the medial eye angle using heparinized glass capillary tubes. Plasma was stored at 20 C for 24 h before transaminase determination, which was carried out using standard laboratory techniques. Production of eicosanoids ex vivo and measurement of their concentrations Samples of liver tissue, kept on ice, were minced into small fragments (12 mm3) in PBS. After sedimentation at unit gravity, the fragments were washed twice in fresh PBS, then transferred into preweighed tubes and centrifuged at 500 g at 4 C for 3 min. The sediment was quickly weighed and resuspended in minimal essential medium (Gibco, Grand Island, New York, USA; 5 }il/mg tissue) and incubated in a water bath at 37C for 1 h. In some experiments KCZ (10_5mol/l), dissolved in 2% dimethylsulphoxide (DMSO), was added to liver tissue fragments (in a volume of 0.1 ml/ml medium) before their incubation for prostaglandin production. Vehiculum was added to control samples in these experiments. After incubation and addition of indomethacin (20u.l/ml), samples were centrifuged as above and the supernatants stored at 70 C until analysis. Concentrations of PGE2, thromboxane A2 (TXA2) and leukotriene C4 (LTC4) in the supernatants were determined using appropriate radioimmunoassay kits [Amersham International, Amersham, Buckinghamshire, UK; PGE2 125I-scintillation proximity assay (RPA539), TXB2 3H assay (TRK780) and LTC4 3H assay (TRK905), respectively], according to the manufacturer's instructions. The bound radioactivity was measured in a liquid scintillation counter. Statistical analysis Results are expressed as means+ SEM. Parametric variables were compared by Student's t-test. Differences in survival between the groups of mice were compared by X2 test, using Yates's correction when indicated. Results The influence of ketoconazole on the survival of mice with acetaminophen-induced hepatitis Mice received saline or KCZ (100 mg/kg) intraperitoneally either 30 min before or 23h after intragastric administration of AAP (300 mg/kg). The survival of mice was followed for 48 h, as our previous results have shown that control mice (given saline before AAP) either die within this period or fully recover and survive indefinitely [9]. Fig. 1 shows the percentage of mice Ketoconazole inhibits acetaminophen-induced hepatotoxicity Culo et al. 759 surviving 48 h after AAP administration. In comparison with control mice given saline, the survival of mice treated with KCZ was better at all time intervals, but was statistically significant only when KCZ was given 30 min before or 2h after AAP administration (P<0.01 and P<0.05, respectively). In some experiments, KCZ (100 mg/kg) was given intragastrically and the protective effect was similar to that observed when given intraperitoneally (data not shown). Therefore, in all further experiments intraperitoneal KCZ was given. The protective effect of KCZ was also tested in a different model of hepatitis (i.e. in mice sensitized to the lethal effect of LPS by DGalN). KCZ given 30 min before DGalN reduced the LPS-induced mortality from 83 to 54%, but the difference was not significant (P>0.05; Table 1). % Saline 0 KCZ -30 min 1 00 -i Fig. 1. Influence of ketoconazole (KCZ) on survival of mice with acetaminophen (AAP)-induced hepatitis. Saline or KCZ (100mg/kg) are given intraperitoneally either 30min before or 2-3 n after AAP administration (300 mg/kg). Survival was recorded after 48 h. *P<0.05; **P<0.01. Plasma aminotransferase levels Plasma AST and ALT levels were measured 24 h after AAP administration (300mg/kg). This interval was chosen because we observed that the levels of AST and ALT are at their peak values at this time (data not shown). KCZ (100 mg/kg) or saline were given either 30 min before or 2 h after AAP administration. In comparison with normal mice, the administration of AAP increased AST and ALT by approximately 17 and 58 times, respectively (Fig. 2). The administration of KCZ at both time intervals significantly reduced the increase of transaminase levels induced by AAP (P<0.05 in comparison with saline-treated mice). To see whether KCZ alone is hepatotoxic, two groups of normal mice were given intraperitoneal KCZ 100 or 300 mg/kg, and aminotransferase levels were determined 24 h later. At a dose of 100 mg/kg, KCZ had no effect on the levels of AST or ALT, while a dose of 300 mg/kg increased the AST level by 65% and ALT by 100% from the basal level in normal mice (data not shown). 1800 1600 1400 40 0 - % AST EJ ALT S 1200 I- 1000 Q. CO  aoo 600 - X 200 - r n Normal mice KCZ (+2 h) W/A Saline KCZ (-30 min) Fig. 2. Plasma transaminase levels in normal mice and in mice with acetaminophen (AAP)-induced hepatitis treated with saline or ketoconazole (KCZ). Saline or KCZ (100 mg/kg) were given intraperitoneally either 30 min before or 2 h after AAP administration (300 mg/kg). Plasma transaminase levels (meanSEM) were determined 24 h after AAP administration (n = 7 to 15). *P< 0.05; **P< 0.01. AST, aspartate aminotransferase; ALT, alanine aminotransferase. Effect of ketoconazole administered in vivo on the production of eicosanoids Eicosanoid production was determined in supernatants of cultured tissue fragments of normal livers and livers from AAP-administered mice pretreated with saline or KCZ (100 mg/kg). In comparison with normal mice, the production of all measured eicosanoids was increased in mice with AAP-induced hepatitis pretreated with saline; PGE2 increased approximately 1.5 times, TXA2 2.0 times and LTC4 2.5 times (Fig. 3). Pretreatment with KCZ further increased the production of PGE2 and LTC4 (2.0 and 1.8 times, respectively, in comparison with saline-pretreated mice with hepatitis), but reduced the production of TXA2 by approximately 50% in comparison with saline-pretreated mice. All these changes in eicosanoid production after KCZ pretreatment were statistically significant (P<0.05). Essentially identical results were obtained in repeated experiments (data not shown). Because the increase in LTC4 after KCZ treatment was rather unexpected, we determined the LTC4 concentration in plasma of identically treated mice. As in culture of liver fragments ex vivo, administration of AAP increased the plasma concentration of LTC4 in comparison with normal mice (LTC4 concentration 672 68 and 252 89 pg/ml, respectively; P< 0.005), and pretreatment with KCZ further increased it (1012+ 71 pg/ml LTC4; P<0.01 in comparison with saline-pretreated mice with hepatitis). 3500 ~\ 3000 2500 - 2000 a 1500 1000 - 500  PGE  Normal Vehiculum 03 KCZ 'A I V/, TxA  // // U % LTC 7000 6000 5000  Treatment of mice Untreated Saline + AAP E3 KCZ + AAP Fig. 4. Effect of ketoconazole (KCZ) administered in vitro on eicosanoid production by the liver fragments. Liver samples were taken 6h after acetaminophen (AAP) administration (300mg/kg), and incubated with vehiculum or KCZ (10-5mol/l) for 1 h. Eicosanoids were determined in the supernatants obtained after incubation. Control group liver fragments were taken from normal AAP-untreated mice. Mean values+ SEM (n = 6). *P<0.05. PGE2, prostaglandin E2; TxA2, thromboxane A2; LTC4, leukotriene C4.  YA / / 2 I - PGE LTC 1000 TxA Fig. 3. Effect of ketoconazole (KCZ) administered in vivo on eicosanoid production by the liver fragments. Saline or KCZ (100 mg/kg) were given 30 min before acetaminophen (AAP) administration (300 mg/kg). Liver samples were taken 6h after AAP administration, and eicosanoid concentration was determined in supernatants of 1 h culture of liver fragments. Mean valuesSEM (n = 6). *P<0.05. PGE2, prostaglandin E2; TxA2, thromboxane A2; LTC4, leukotriene C4. Effect of ketoconazole administered in vitro on the production of eicosanoids Mice were given intragastric AAP (300 mg/kg). Six hours after AAP administration, fragments of liver tissue were incubated with KCZ (10~5mol/l) or vehiculum for 1 h. This concentration of KCZ has been shown to be effective in modulating prostaglandin-synthesis in vitro in several models [5,7]. Eicosanoid production was determined in the supernatants obtained after incubation. Liver fragments of mice with AAP-induced hepatitis incubated with vehiculum produced increased quantities of all measured prostaglandins in comparison with the livers of normal mice (Fig. 4). Similar to the results obtained after the administration of KCZ in vivo, the addition of KCZ to liver fragments from AAP-treated mice in vitro significantly increased PGE2 and reduced TXA2 production (P<0.05 in comparison with the same liver fragments incubated with vehiculum). However, contrary to the results obtained after the administration of KCZ in vivo, the addition of KCZ in vitro inhibited the synthesis of LTC4 by liver fragments from AAP-treated mice (P<0.05, compared with the same samples incubated with vehiculum). Ketoconazole inhibits acetaminophen-induced hepatotoxicity Culo eta/. Discussion Our results indicate that KCZ reduces mortality and hepatic injury in mice with acute AAP-induced hepatitis. Theoretically, there are several mechanisms by which KCZ might act beneficially in this model. First, because KCZ binds to and interferes with cytochrome P-450 enzymes [11], it may also interfere with the metabolism of AAP in the liver. It is generally considered that under the action of the P-450 monooxygenase system, AAP is transformed into an active (hepatotoxic) compound N-acetyl-p-benzoquinone imine in the liver [8,12], although some data show that the parental compound is also active [13]. It is believed that this reactive electrophylic metabolite binds covalently to hepatic macromolecules thus causing hepatotoxicity [12]. The interference with AAP transformation into an active moiety is probably not the major protective mechanism of KCZ, because KCZ was effective when administered 2h after AAP (Fig. 1), at the time when the bulk of AAP administered had already transformed into the active form [10]. Furthermore, KCZ was moderately protective in the DGalN/LPS model of hepatitis (Table 1), in which hepatic injury was inflicted by a metabolic process (disturbance) independent of the cytochrome P-450 system activation [14]. The protective effect of KCZ might be based on its modulating effect on the synthesis of eicosanoids in the liver. KCZ stimulates the synthesis of PGE2 and inhibits the synthesis of TXA2 in the liver from AAP-treated mice. The same results were obtained when KCZ was injected to mice or the drug added to liver fragments in vitro (Figs 2 and 3). These data are in agreement with those of Tolman and Fuller [7], who have shown that KCZ stimulates PGE2 and PGD2 synthesis and inhibits TXA2 synthesis by human platelets and guinea pig lungs in vitro. PGE2 has been shown to be protective in rodents with AAP-induced [9] and other forms of hepatitis [15,16]. PGE2 is also a radioprotective agent [17]. On the other hand, increased production of TXA2 is believed to be one of the main pathogenic mechanisms in toxic hepatitis [10,18]. Another eicosanoid, the synthesis of which is modulated by KCZ in AAP-treated liver, is LTC4. KCZ has been shown to inhibit the synthesis of LTC4 by human polymorphonuclear cells in vitro [5,19]. On the basis of these findings in vitro, KCZ is considered a relative specific inhibitor of 5-lipoxygenase [5] and was used for the study of the role of 5-lipoxygenase product in vitro [20] and in vivo [21]. However, our results showed KCZ to have different effects on LTC4 synthesis in vitro and in vivo; it inhibited LTC4 synthesis when added to liver fragments in vitro, but increased LTC4 concentration in serum of mice when given in vivo. These data should be reconciled with data on the bronchodilatatory effect of KCZ in antigen-induced bronchoconstriction in guinea pigs, which imply the inhibitory action of KCZ on synthesis of leukotrienes in vivo [5]. However, some proinflammatory effects of KCZ in a model of hamster periodontitis could easily be explained by the same effect [21]. Although leukotrienes have been shown to be important mediators in endotoxin-induced hepatic injury [22,23], LTC4 is a radioprotective agent [24] and might have the same protective effect in our model of hepatotoxicity. However, before any firm conclusion about the role of modulated eicosanoid synthesis in KCZ hepatoprotective effect, one should obtain data with use of specific antibodies to prostaglandins or specific inhibitors of their synthesis in this model. In summary, the protective effect of KCZ in AAP-induced hepatitis is not entirely clear. It is most probably mediated by modulation of eicosanoid synthesis by liver cells. KCZ increases the synthesis of PGE2 and PGI2, which are known for their hepatoprotective effect, and inhibits the production of TXA2, which is believed to be a pathogenic factor in hepatitis. The role of LTC4 in these processes is unclear, since KCZ increases LTC4 concentration in serum and inhibits its synthesis by the liver in vitro. Acknowledgements We are grateful to pharmaceutical companies Krka (Novo Mesto, Slovenia) and Belupo (Koprivnica, Croatia) for donation of pure substances of acetaminophen and ketoconazole, respectively. References De Coster R, Coene MC, Haelterman C, Beerens D, Coeminne N: Effects of high-dose ketoconazole treatment on adrenal min-eralocorticoid biosynthesis in dogs and rats. Acta Endocrinol (Copenh) 1987, 115:423-431. Sonino N: The use of ketoconazole as an inhibitor of steroid production. N Engl ) Med 1987, 317:812-818. Butman SM, Wild )C, Nolan PE, Fagan TC, Finley PR, Hicks MJ, et al.\ Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation. ) Heart Lung Transplant 1991, 10:351-358. Vanden Bossche H, Willemsens G, Cools W, Marichal P, Lauw-ers W: Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and triazoles. Biochem Soc Trans 1983, 11:665-667. Beetens JR, Loots W, Somers Y, Coene MC, De Clerck F: Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo. Biochem Pharmacol 1986, 35:883-891. Maclntyre JP, Pope Bt: The involvement of protein kinase C, calcium, and 5-lipoxygenase in the production of tumor necrosis factor by a cloned interleukin-3-dependent cell line with natural cytotoxic activity. Int ) Immunopharm 1991, 13:175-184. Tolman EL, Fuller BL: Inhibition of thromboxane synthesis in guinea pig lung and human platelets by clotrimazole and other imidazole antifungals. Biochem Pharmacol 1983, 32:3488-3490. Dahlin DC, Miwa GT, Lu AVH, Nelson SD: N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 1984, 81:1327-1331. Renic M, Culo F, Bilic A, Culjak K, Sabolovic D, Jagic V: Protection of acetaminophen-induced hepatotoxicity in mice by prostaglandin E2. Croat j Gastroenterol Hepatol 1992, 1:59-64. Guarner F, Boughton-Smith NK, Blackwell GJ, Moncada S: Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse. Hepatology 1988, 8:248-253. Lavrijsen K, Van Houdt J, Thijs D, Meuldermans W, Heykants J: Interaction of miconazole, ketoconazole and itraconazole with rat-liver microsomes. Xenobiotica 1987, 17:45-57. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette )R, Brodie BB: Acetaminophen-induced hepatic necrosis. Role of drug metabolism. ) Pharmacol Exp Ther 1973, 187:185-194. Esterline RL, Dev Ray S, Ji S: Reversible and irreversible inhibition of hepatic mitochondrial respiration by acetaminophen and its toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Biochem Pharmacol 1989, 38:2387-2390. 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Gibert C, Puig L, Fernandez E, Vila L: Inhibitory effect of bifon-azole, clotrimazole and ketoconazole on polymorphonuclear leucocytes 5-lipoxygenase and platelet thromboxane synthase [abstract]. In 7th International Conference on Prostaglandins and Related Compounds. Abstract Book. Florence: Fondazione Giovanni Lorenzini; 1990:139. Spriggs DR, Sherman ML, Imamura K, Mohri M, Rodriguez C, Robbins G, et a/.: Phospolipase A2 activation and auto-induction of tumor necrosis factor gene expression by tumor necrosis factor. Cancer Res 1990, 50:7101-7107. Baroukh B, Saffar JL: Leukotriene inhibition in hamster periodontitis. A histochemical and morphometric study. Mediators Inflamm 1992, 1:335-339. Tiegs G, Wendel A: Leukotriene-mediated liver injury. Biochem Pharm 1988, 37:2569-2573. Keppler D, Hagmann W, Rapp S, Denzlinger C, Koch HK: The relation of leukotrienes to liver injury. Hepatology 1985, 5:883-891. 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PAGE758 European Journal of Gastroenterology & Hepatology 1995, Vol 7 No 8 PAGE2 European Journal of Gastroenterology & Hepatology 1995, Vol 7 No 8 PAGE758 European Journal of Gastroenterology & Hepatology 1995, Vol 7 No 8 PAGE4 European Journal of Gastroenterology & Hepatology 1 995, Vol 7 No 8 PAGE760 European Journal of Gastroenterology & Hepatology 1 995, Vol 7 No 8  Treatment^No. survived/total (%)tSaline4/25 (1 7)KCZ10/22(46) Table 1. Influence of ketoconazole (KCZ) on survival of mice with hepatitis induced with D(+)-galactosamine hydrochloride (DGalN) and lipopolysaccharide (LPS)*. *Mice were given 650 mg/kg intraperitoneal DGalN and 1 h later 0.01 mg/kg (0.2 (ig per mouse) intraperitoneal LPS. Valine or KCZ (100mg/kg) were given intraperitoneally 30min before DGalN administration. +Survival was recorded after 24 h (pooled data from two experiments). 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