• Toxicological Research
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• v.11 no.2
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• pp.267-271
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• 1995

A single large dose of ethanol as well as chronic ethanol consumption produces alcoholic fatty liver in human and experimental animals. We examined the effects of YH439, a potential hepatoprotective agent, on alcoholic fatty liver generation in adult female rats. In rats treated with YH439 (250 mg/kg, po) 4 hr prior to a single dose of ethanol (6 g/kg, po), a significant decrease in hepatic triglyceride accumulation was observed. YH439 also has an inhibitory effect on hepatic triglyceride and cholesterol accumulation induced by repeated ethanol treatments for one week. Because it has been known that induction of alcoholic fatty liver is associated with lipid peroxidation and/or hepatic glutathione depression, the effect of YH439 on these parameters was determined in the livers of rats treated with ethanol. Coadministration with YH439 inhibited MDA formation and gIutathione depression induced by acute or repeated ethanol administration. In order to determine the effect of YH439 on ethanol metabolism in vivo, disappearance of ethanol from blood was measured. In rats treated with a single dose of ethanol (6 g/kg, po), the ethanol concentration in blood reached a peak approximately 120 min following the treatment which declined linearly for 18 hrs. YH439 had no effect on the decline of blood ethanol concentration regardless of the dose of ethanol given to rats. These results in this study suggest that YH439 has an inhibitory effect on fatty liver generation induced by acute or repeated ethanol consumption through a mechanism not directly related to the rate of ethanol metabolism in vivo.

• The Korean Journal of Pharmacology
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• v.32 no.3
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• pp.407-416
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• 1996

The reactive intermediates formed during the metabolism of therapeutic agents, toxicants and carcinogens by cytochromes P450 are frequently capable of covalently binding to tissue macromolecules and causing tissue damage. It has been shown that YH439, a congener of malotilate, is effective in suppressing hepatic P450 2E1 expression. The present study was designed to further establish the mechanistic basis of YH439 protection against toxicant by assessing its effects against chemical-mediated potentiated hepatotoxicity. Retinoyl palmitate (Vit-A) pretreatment of rats for 7 days substantially enhanced carbon tetrachloride hepatotoxicity, as supported by an ${\sim}5-fold$ increase in serum alanine aminotransferase (ALT) activity, as compared to $CCl_4$ treatment alone. The elevation of ALT activity due to Vit-A was completely blocked by the treatment of $GdCl_3$ a selective inhibitor of Kupffer cell activity. Concomitant pretreatment of rats with both YH439 and Vit-A resulted in a 94% decrease in Vit-A-potentiated $CCl_4$ hepatotoxicity. YH439 was also effective against propyl sulfide-potentiated $CCl_4-induced$ hepatotoxicity. Whereas propyl sulfide (50 mg/kg, 7d) enhanced $CCl_4-induced$ hepatotoxicity by >5-fold, relative to $CCl_4$ treatment alone, concomitant treatment of animals with both propyl sulfide and YH439 at the doses of 100 and 200 mg/kg prevented propyl sulfide-potentiated $CCl_4$ hepatotoxicity by 35% and 90%, respectively. Allyl sulfide, a suppressant of hepatic P450 2E1 expression, completely blocked the propyl sulfide-enhanced hepatotoxicity, indicating that propyl sulfide potentiation of $CCl_4$ hepatotoxicity was highly associated with the expression of P450 2E1 and that YH439 blocked the propyl sulfide-enhanced hepatotoxicity through modulation of P450 2E1 levels. Propyl sulfide- and $CCl_4-induced$ stimulation of lipid peroxidation was also suppressed by YH439 in a dose-related manner, as supported by decreases in malonedialdehyde production. The role of P450 2E1 induction in the potentiation of $CCl_4$ toxicity and the effects of YH439 were further evaluated using pyridine as a P450 2E1 inducer. Pyridine pretreatment substantially enhanced the $CCl_4$ hepatotoicity by 23-fold, relative to $CCl_4$ alone. YH439, however, failed to reduce the pyridine-potentiated toxicity, suggesting that the other form(s) of cytochroms P450 inducible by pyridine, but not suppressible by YH439 treatment, may play a role in potentiating $CCl_4-induced$ hepatotoxicity. YH439 was capable of blocking cadmium chloride-induced liver toxicity in mice. These results demonstrated that YH439 efficiently blocks Vit-A-enhanced hepatotoxiciy through Kupffer cell inactivation and that the suppression of P450 2E1 expression by YH439 is highly associated with blocking of propyl sulfide-mediated hepatotoxicity.

• Archives of Pharmacal Research
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• v.20 no.6
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• pp.629-632
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• 1997

The pharmacokinetics of YH439 and its metabolites were investigated after oral administration of YH439 to rats to investigate the food effect. After oral administration of YH439, its metabolites, M4 and M5 were detected in plasma. YH439 was not detected in the plasma for both fasted and fed rats for all doses studied. The pharmacokinetic parameters of the metabolites were not affected by food at all doses studied. The results of this study indicated that there are no significant food effects on the pharmacokinetics of YH439 and its metabolites in rats.

• YAKHAK HOEJI
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• v.43 no.2
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• pp.198-207
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• 1999

The aim of the present investigation was to examine whether YH439, a hepatoprotective agent, exerts protective effect against hepatotoxicity and reduces the production of cytokines and NO in lipopolysaccharide (LPS)-primed rats with carbon tetrachloride ($CCl_4$). Administration of LPS following a single dose of CCl4 injection resulted in remarkable elevations of the serum $TNF{\alpha},{\;}IL-l{\beta$ and IL-6 level. The serum NO level was moderately elevated and severe liver damage was evidenced by increases in serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities. YH439 decreased the levels of TNF, $IL-l{\beta}$, IL-6, ALT, SDH as well as NO in the serum elevated by CCl4+LPS in a dose-dependent manner. Inducible nitric oxide synthase (iNOS) level was decreased in the liver of rats treated with YH439. The increased iNOS activity induced by LPS and $interferon-{\gamma}$ was significantly decreased in RAW 264.7 cells by YH439 treatment. YH439 increased the GSH level decreased by $CCl_4+LPS$ and suppressed the ratio of GSSG/GSH. The reduction of hepatotoxicity by YH439 may associated with the decrease in the production of cytokines as well as suppression of iNOS protein in conjunction with an increase in the GSH level.

• Archives of Pharmacal Research
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• v.24 no.6
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• pp.584-589
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• 2001

Isopropryl 2-(1-3-dithiethane-2-ylidene)-2 [N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439) is currently under phase ll clinical trials by the Yuhan Research Center for use as a hepatoprotective agent. Unfortunately, the oral bioavailbility of YH439, which is sparingly soluble in water (i.e., $0.3{\;}\mu\textrm{g}/ml{\;}or{\;}0.91{$\mu}M$ at room temperature), reportedly, is negligibleregardless of the dose administered to rats in the 10-300 mg/kg range. The bioavailability of the compound increased up to 24%, when administered in the form of a micellar solution ($700{\;}\mu\textrm{g}/ml$or 2.1 mM for YH439) at a dose of 10 mg/kg, suggesting that its limited solubility is associated with its negligible bioavailability. In order to obtain additional informmation concerning the bioavailability of YH439, the mechanism(s) involved in gastrointestinal (Gl) absorption were investigated in the present study. For this purpose, the transport of YH430 across a Caco-2 cell monolayer was measured in a $Transwell^{\circledR}$. A permeability of $4.07{\times}10^{-5}{\;}cm/s$ was obtained for the absorptive (i.e., apical to basolateral direction) transport of $0.42{\mu}M$ YH439, implicating that the in vivo Cl absorption is nearly complete. The absorptive transport exhibited a slight concentration-dependency with an intrinsic clearance ($CL_{i}$) of $0.38{\mu}L/{\textrm{cm}^2}/sec$, which accounted for 28.1% of the total intrinsic clearance (i.e., $CL_i$ plus the intrinsic clearance for the linear component) of the transport. Thus, saturation of the absorption process appears to be a minor factor in limiting the bioavailability of the compound. The apparent permeability of YH439 from the basolateral to the apical direction (i.e., efflux, $6.67{\times}10^{-5}{\;}cm/s$) was comparable to that for absorptive transport, but, interestingly, a more distinct concentration-dependency was observed for this transport. However, the efflux does not appear to influence the bioavailability of the compound, as evidenced by the sufficiently high permeability in the absorption direction. Rather, a reportedly extensive first-pass hepatic metabolism appears to be a principal factor in limiting the bioavailability. In this respect, reducing the first-pass metabolism by some means would lead to a higher bioavailability of the compound. Thus, elevation of the absorption rate of YH439 becomes a necessity. From a practical point of view, increasing the concentration of YH439 in the Cl fluid appears to be a feasible way to increase the absorption rate, because the compound is primarily absorbed via a linear mechanism. In summary, the solubilization of YH439, as previously demonstrated for a micellar solution of the compound, appears to be a practical way to increase the oral bioavailability of YH439.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1995.04a
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• pp.105-105
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• 1995

새로운 간장질환 치료제로 개발중인 YH439가 orotic acid, nicotinamide 및 ethionine에 의해 유발되는 지방간에 대한보호 및 치료효과를 관찰하였다. 웅성 SD계 rat에 orotic acid(1%) 또는 nicotinamide(2%)가 첨가된 사료를2주간 섭취시켜 유발된 지방간에 대한 YH439의 보호 및 치료효과와 ethionine(100mg/kg, i.p.)투여로 유도되는 지방간에 대한 YM439의 보호효과를 관찰하기 위하여 간 조직 중 triglyceride, cholesterol 및 phospholipid의 함량을 측정하여 비교하였다. 그 결과, erotic acid 또는 nicotinamide의 섭취로 인해 랫드의 간 조직 중 triglyceride, cholesterol 및 phospholipid의 함량은 1.5-3배정도 증가하였으며, 이 증가된 지질들은 YH439 100, 200mg/kg 투여에 의해 유의성 있게 억제되었다. 또한 ethionine투여에 의해서도 랫드의 간 조직 중 triglyceride, cholesterol 및 phospholipid의 함량은 약 2배정도 증가되었으며, YH439 전저치에 의해 이 현상들이 억제되는 효과를 나타내었다.

• Archives of Pharmacal Research
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• v.28 no.3
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• pp.330-334
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• 2005

The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 $\mu$mol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance ($CL_b$) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane ($CL_{exc}$) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent V$_{max}$ and $CL_{linear}$, but the $K_m$ for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.

• Toxicological Research
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• v.11 no.2
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• pp.273-277
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• 1995

Several metabolic modulators on the generation of carbon monoxide (CO)from dichloromethane (DCM) was examined in adult female rats. It has been known that DCM is converted to CO by cytochrome P-450 or to carbon dioxide $(CO_2)$ by glutathione-dependent metabolic reaction. In rats treated with DCM (3 mmol/kg, ip) only, the carboxyhemoglobin (COHb) level reached a peak of approximately 10% 2 or 3 hr following the treatment. Disulfiram (300 mg/kg, ip) or allylsulfide (200 mg/kg, po), both known as a selective inhibitior for cytochrome P-450 2E1, blocked the increase in COHb concentratlons almost completely suggesting that the metabolic conversion of DCM to CO is mediated by the activity of this specific type of isozyme. YH439 (125 or 250 mg/kg, po), a potential hepatoprotective agent, decreased the COHb elevation as well indicating that this chemical is a potent inhibitor for 2E1. In rats treated with pyrazine (200 mg/kg, ip) 18 hr prior to DCM the peak COHb concentration was decreased by approximately 3 or 4%. However, pretreatment of rats with pyrazine either 24 or 48 hr before DCM increased the peak COHb concentration significantly compared to the rats treated with DCM only. The results in the present study strongly suggest that the generation of CO from DCM depends on the 2E1 activity and that the pharmacological and/or toxicological action of YH439 or pyrazine in animals or human is associated with its effect on this isozyme.

• Toxicological Research
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• v.9 no.2
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• pp.167-175
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• 1993

Protective effects of dithiol malonate derivatives (DMDs), YH-100, YH-150 and YH-439 on carbon tetrachloride-induced hepatotoxicity were investigated in primary rat hepatocytes culture. Treatment of DMDs to hepatocytes culture did not affect total cytochrome P-450 content and ECOD and AHH activities. Protein and RNA synthesis was also similar to control. Meanwhile, DMDs significantly decreased LDH release and in vitro lipid peroxidation induced by $CCI_4$. Accumulation of cellular triglyceride and decreased secretion of VLDL from liver cells by $CCI_4$ treatment were also significantly protected.

• 대한임상약리학회:학술대회논문집
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• 1996.12a
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• pp.42-43
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• 1996