KR100408107B1 - Pharmaceutical compositions for protecting liver comprising leucocyanidin - Google Patents

Abstract

The present invention relates to the use of leucocyanidin as a medicament for liver protection. The present invention provides a method of using leucocyanidine and a pharmaceutical composition thereof for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic. The present invention also provides a pharmaceutical composition and a method of using leucocyanidine in addition to acetaminophen to inhibit hepatotoxicity caused by hepatotoxic substances metabolized to toxic bodies by phase I metabolic enzymes. According to the present invention, liver damage caused by hepatotoxic substances can be significantly reduced. The present invention can be applied to suppressing (reducing) the toxicity of not only substances metabolized by phase I metabolizing enzymes, but also all substances whose excretion rate is promoted by phase II metabolizing enzymes.

Description

Pharmaceutical composition for liver protection containing leucocyanidine {PHARMACEUTICAL COMPOSITIONS FOR PROTECTING LIVER COMPRISING LEUCOCYANIDIN}

The present invention relates to new medicinal uses of leucocyanidin. Specifically, the present invention relates to the use of leucocyanidin as a medicament for liver protection. More specifically, the present invention relates to a method of using leucocyanidine for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic and a pharmaceutical composition therefor. The present invention also relates to a method for using leucocyanidins for inhibiting liver toxicity by a hepatotoxic substance which is metabolized into a toxic body by first phase metabolic enzymes, in addition to acetaminophen, and a pharmaceutical composition therefor.

Leucocyanidin is one of the trocyanidol oligomers contained in grape ( Vitis vvinifera ) seed extract and is a compound having the following structural formula:

The leucocyanidins are known to have a vascular damage protection effect, an antioxidant action, and a mutation inhibiting effect. Masquelier, J .: Oligomeres procyanidoliques. Perfumes, cosmetiques, aromes Oct-Nov, 89-97, 1997; Facino, RM, Carini, M., Aldini, G., Bombardelli, E., Morazzoni, P. and Morelli, R .: Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. Drug Res. (Germany) 44 (1), 5, 592-601, 1994; Nuttall, SL, Kendall, MJ, Bombardelli, E., and Morazzoni, P .: An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect, J. Clin. Pharm. Ther. 23 (5), 385-389, 1998; Morazzoni, P. and Bombardelli, E .: Antimutagenic activity of procyanidins from Vitis vinifera, Fitoterapia LXV (3), 203-208, 1994].

On the other hand, acetaminophen is a drug widely used as an antipyretic analgesic and has been shown to be hepatotoxic when used in high doses [Davidson, D. G. D. and Eastham, W. N .: Acute liver necrosis following overdose of paracetamol.Br. Med. J.2 497-499, 1966; Boyd, E. M. and Bereezky, G. M ,: Liver necrosis from paracetamol.Br. J. Pharmacol.Chemother. 26, 606-614, 1966. Acetaminophen is excreted in the body primarily through phase II metabolic reactions, such as glucuronic acid conjugation and sulfuric acid conjugation [Reference: Nelson, S. D .: Metabolic activation and drug toxicityJ. Med. Chem.25, 753-765, 1982.

On the other hand, N-acetyl-p-benzoquinoneimine (NAPQI) produced by phase I metabolic reaction of acetaminophen is an active body showing hepatotoxicity, which is excreted and detoxified by a glutathione reaction reaction [Corcoran, G.B., Mitchell, JR, Vaishnav, YN and Horning, EC: Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-Acetyl-p-Benzoquinoneimine. Mol. Pharmacol. 18, 536-542, 1980]. Therefore, excessive administration of acetaminophen not only saturates the glucuronic acid synthesis and sulfuric acid synthesis reactions, but also consumes hepatocyte glutathione, and the NAPQI produced in excess binds to proteins (enzymes) and DNA, which are intracellular polymers. This will cause liver damage.

The inventors of the present invention found that hepatic toxicity by a wide variety of substances activated by phase I metabolism in the liver, resulting in phase II inhibition of enzyme activity that metabolizes the substance itself into the toxic body and promotes excretion of the toxic substance The present invention was found to be possible by increasing the activity of the enzyme and to complete the present invention.

Accordingly, it is an object of the present invention to provide a method for inhibiting liver damage by liver toxic substances and a pharmaceutical composition therefor.

Another object of the present invention is to provide a method for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic and a pharmaceutical composition therefor.

Still another object of the present invention is to provide a method for inhibiting liver toxicity by a hepatotoxic substance other than acetaminophen, which is metabolized to a toxic body by phase I metabolic enzymes, and a pharmaceutical composition therefor.

1 is a micrograph for comparing normal liver with liver necrosis by acetaminophen administration,

1A is a liver lobule photograph (50 magnification) of a control mouse,

1B is a photograph of liver lobule (50 magnification) of 150 mg / kg / day leucocyanidine alone group mice,

1C is a micrograph (100 magnification) of liver necrosis grade 1 by acetaminophen administration,

1D is a micrograph (50 magnification) of liver necrosis grade 2,

1E is a micrograph (50 magnification) of liver necrosis grade 3,

1F is a micrograph (50 magnification) of liver necrosis grade 4. FIG.

Figure 2 is a graph showing the effect of leucocyanidine on the activity of P450 1A1 in rat liver, the activity of the enzyme is expressed as the amount of lesorupin production (nmol) / min / mg (protein).

Figure 3 is a graph showing the effect of leucocyanidine on the activity of P450 1A2 in rat liver, the activity of the enzyme is shown as the amount of lesorupin production (nmol) / min / mg (protein).

4 is a graph showing the effect of leucocyanidine on the activity of P450 2B1 in rat liver, the activity of the enzyme is expressed as the amount of lesorupin production (nmol) / min / mg (protein).

5 is a graph showing the effect of leucocyanidine on the activity of P450 3A4 in rat liver, the activity of the enzyme is shown as formaldehyde production (pmol) / min / mg (protein).

6 is a graph showing the effect of leucocyanidin on the activity of P450 2E1 in rat liver, the activity of the enzyme is shown as formaldehyde production (nmol) / min / mg (protein).

FIG. 7 is a graph showing the effect of leucocyanidine on the total amount of chitochrome P450 in rat liver, in which the enzyme content is expressed as nmol / mg (protein).

8 is a graph showing the effect of leucocyanidine on the activity of GST in rat liver, the activity of the enzyme is shown as CDNB-GS production (μmol) / min / mg (protein).

9 is a graph showing the effect of leucocyanidine on the activity of PST in rat liver, and the activity of the enzyme is expressed as β-naphthyl sulfate production amount (nmol) / min / mg (protein).

The above object of the present invention is achieved by using leucocyanidin as a liver protectant to inhibit the activity of phase I metabolic enzymes involved in the metabolism of hepatotoxic substances and to activate phase II metabolic enzymes.

Accordingly, the present invention provides a pharmaceutical composition for protecting liver, comprising an effective amount of leucocyanidine and a pharmaceutically acceptable carrier to inhibit liver damage.

According to one preferred embodiment of the present invention, the pharmaceutical composition can be used to suppress liver toxicity by acetaminophen. According to another embodiment, the pharmaceutical composition of the present invention can be used to suppress liver toxicity by liver toxic substances that are metabolized into toxic bodies by phase I metabolic enzymes. The phase I metabolic enzyme is preferably chitochrome P450 1A1, 1A2, 2B1, 3A4 or 2E1.

According to another exemplary embodiment of the present invention, the pharmaceutical composition may be used to suppress liver toxicity caused by hepatotoxic substances whose excretion rate is accelerated by phase II metabolic enzymes. Phase II metabolic enzymes are preferably phenol sulfotransferase (PST) and glutathione S-transferase (GST).

The effective amount of leucocyanidine is at least in part dependent on the extent of liver damage in the subject to which the desired liver protective effect can be achieved, but is generally from 0.1 to 1500 mg per kg body weight per day, preferably from 10 to 1000 mg, more preferably 20 to 500 mg, most preferably 50 to 150 mg.

The pharmaceutical composition of the present invention may be formulated into tablets, capsules, granules, powders, syrups, solutions, emulsions, suspensions, injections, capsules, pills and the like according to methods known in the art. Pharmaceutically acceptable carriers suitable for use in formulating the pharmaceutical compositions of the invention include any and all solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, fungicides, antibacterial agents, isotonic agents commonly used in the pharmaceutical arts. And absorption retardants. The use of such carriers in pharmaceutically active ingredients is known in the art and described, for example, in Remington's Pharmaceutical Sciences, 18th edition, McPublisher, Pennsylvania, USA. Except incompatibility with the active ingredient, any carrier may be used to prepare the pharmaceutical composition of the present invention. Supplementary active ingredients can also be added to the pharmaceutical compositions. The proportion of the active ingredient combined with the pharmaceutically acceptable carrier can be readily determined empirically by those skilled in the art.

The pharmaceutical composition of the present invention can be administered orally or parenterally to an animal, preferably a human, in need of liver protection. It is preferred to administer orally before the drug causing the liver toxicity, for example acetaminophen, for example one week before.

Example

The following is intended to explain the present invention in more detail based on examples, but the present invention is not limited thereto.

The results of each example were shown using the one way analysis of variance to verify the statistical significance of all indicators and with p <0.05 as the significance limit.

Example 1

Evaluation of Hepatoprotective Effects

This example shows how the activities of phase I and II enzymes change by administration of leucocyanidine and through in vivo testing whether these enzymes inhibit the toxicity of acetaminophen induced by the toxic body. It is to confirm. Toxicity reduction of acetaminophen is associated with the activity of serum transaminase (ALT) and aspartate aminotransferase (AST) enzymes that leak into the blood due to liver damage caused by high doses of acetaminophen. And the inhibitory effect of leucocyanidins on resulting liver tissue necrosis.

(1) animal kills

35-40 g male ICR-mouse is orally given the same amount of propylene glycol as used to dissolve leucocyanidine (LC; 50, 100, 150, mg / kg / day) or leucocyanidine for 7 days. And acetaminophen (400 mg / kg) dissolved in saline was administered intraperitoneally. After 18 hours, mice were anesthetized with diethyl ether, and blood was drawn from the abdominal vein and the liver was dissected.

(2) Alanine Aminotransferase (sALT)

Whole blood was left at room temperature for 30 minutes, and at 4 ° C., centrifuged at 3,000 rpm for 10 minutes to separate serum. ALT activity in serum was used ALT reagent (Sigma Chemical Corporation).

(3) histopathological examination

Paraffin sections of the liver were fixed with neutral 10% formalin and then stained with hematoxylin and eosin (HE). Liver sections were usually analyzed by light microscopy.

Results-Protective effect on acetaminophen-induced liver toxicity and mortality

(1) mortality

Mice were pretreated with LC for 7 days and 400 mg / kg intraperitoneal injection of acetaminophen on day 8, and mortality was observed for 18 hours after acetaminophen administration, and acetaminophen alone, LC 50, 100, 150 mg / kg Mortality in the pretreatment group was as shown in Table 1 below.

Effect of LC on Acetaminophen-induced Mortality Test group death rate(%) Acetaminophen alone 70 LC 50 mg / kg pretreatment 40 LC 100 mg / kg pretreatment 40 LC 150 mg / kg pretreatment 20

As can be seen from the table, it can be seen that the mortality due to the toxicity of acetaminophen decreases in a LC dose dependent manner.

(2) liver damage

Mice were administered acetaminophen and liver tissue was observed under a microscope, and the extent of liver damage was shown using a scoring system from grade 1 (FIG. 1C) to grade 4 (FIG. 1D). From the micrograph shown in FIG. 1, hepatic necrosis by acetaminophen administration can be compared with normal liver. Normal livers are shown as grade 0 (FIG. 1A). As a result of testing for 10 groups, the number of animals corresponding to each grade was as shown in Table 2 below.

Effect of LC on Acetaminophen-Induced Liver Necrosis Test group (dosage mg / kg) Liver necrosis grade 0 One 2 3 4 Control 10 - - - - Acetaminophen (AA) alone - 2 One - 7 LC (150) only 10 - - - - LC (50) + AA - 3 - One 6 LC (100) + AA - 3 One One 5 LC (150) + AA 3 3 2 - 2

As can be seen from the table, 70% of acetaminophen alone group showed severe necrosis of grade 4, and LC 100, 150 mg / kg group showed 60%, 20% grade 3 or 4 necrosis. , 30% showed no liver necrosis in the 150 mg / kg group. From these results, it can be seen that liver necrosis is suppressed in LC dose-dependent manner.

(3) serum ALT enzyme activity

ALT activity in serum of each test group was as shown in Table 3 below.

Effect of LC on Acetaminophen Induced sALT Grade Test group (dosage mg / kg) ALT activity in serum (U / L) <40 40-100 100 1000 Survival / Total Control 10 - - - 10/10 Acetaminophen (AA) alone - One 2 - 3/10 LC (50) + AA - One 3 2 6/10 LC (100) + AA - One 2 3 6/10 LC (150) + AA One 4 2 One 8/10

As can be seen from the above table, in the acetaminophen alone group, blood ALT activity was significantly increased in comparison with the normal group, but most of them died. In the LC-administered group, a significant inhibitory effect on liver toxicity was observed in the 150 mg / kg / day-administered group. Indicated.

Example 2

Effect of Leucocyanidins on Enzyme Activity

In this example, the inhibitory effect on the hepatotoxic substances metabolized to the toxic body by these enzymes other than acetoaminophen by looking at the activity changes of the Phase I and II metabolizing enzymes by leucocyanidine administration do.

(1) animal kills

200-250 g of male SD-rat were orally administered the same amount of propylene glycol as was used to dissolve leucocyanidine (LC; 50, 100 mg / kg) or leucocyanidine for 7 days. After 24 hours rats were anesthetized with pentobarbital (50 mg / kg, intraperitoneal) and bled to death.

(2) Separation of liver cytosol and microsomes

Blood was removed from the abdominal vein, then washed with ice-cold 0.9% saline and incised to weigh. Liver microsomes and cytosol were prepared as follows. A portion of liver was homogenized with cold 0.1 M Tris-KCI buffer (pH 7.4) containing 1 mM EDTA. The homogenate was centrifuged at 10,000 × g for 40 minutes and the supernatant was ultracentrifuged at 105,000 × g for 60 minutes. The supernatant was used as a fraction of cytosol enzyme. The precipitate was resuspended in the buffer used for homogenization and then ultracentrifuged again. After removing the supernatant, the precipitate was suspended in 50 mM Tris-buffer (1 mM EDTA, 20% glycerol, pH 7.4) or 0.1 M calcium phosphate buffer (20% glycerol, pH 7.4). All centrifugation procedures were performed at 4 ° C. and all samples were stored at −70 ° C. until measurement.

(3) enzyme measurement method

(i) Ethoxyresorupine 0-Dealkylating Agent

Ethoxyresorufine O-dealkylating agent (P450 1A1) activity is described by Rubet et al., Lubet, RA, Mayer, RT, Cameron, JW, Nims, RW, Burke, MS, Wolfe, T. and Guengerich, FP: Dealkylation of pentoxyresorufin: a raped and sensitive assay for measuring induction of cytochrome (s) P-450 by phenobarbital and other xenobiotics in rat. Arch. Biochem. Biophys. 238, 43-48, 1985] was determined by the fluorescence measurement of the amount of lesorupine produced. The reaction mixture was made with 5 mM Tris-HCl (pH 8.4), 5 mM MgCl ₂ , 0.5 mM NADP, 7.5 mM DL-isocitric acid, 1 unit of isocitric acid dehydrogenator, 1 mg microsome protein. After pre-incubation for 5 minutes at 37 ℃ shaking well, 5 μM 7-ethoxy resorphin was added and incubated for 10 minutes at 37 ℃ shaking well. The reaction was terminated by addition of 5% ZnSO ₄ and saturated barium hydroxide. The mixture was then centrifuged at 4 ° C. at 3,000 × g for 10 minutes. Two-fold doses of 0.5 M glycine-NaOH (pH 8.5) were added to the algal supernatant. The increase in fluorescence was recorded for 4-5 minutes (excitation wavelength = 535 nm, emission wavelength = 582 nm). Enzyme activity was measured compared to the resorphin standard curve.

(ii) Methoxyresorufine O-Dealkylating Agent and Penthoxy Resorphin O-Dealkylating Agent

The methoxy resolupine O-dealkylating agent (P450 1A2) and pentoxy resorphin O-dealkylating agent (P450 1B1) activity are the same except that the substrate concentration is 5 μM of methoxy resolupine and 10 μM of pentoxyresolupine. , Was measured in the same manner as described in the ethoxyresorufine O-dealkylating agent analysis.

(iii) N-nitrosodimethylamine N-demethylating agent

N-nitrosodimethylamine N-demethylating agent (P450 2E1) activity is described by Sohn et al., Sohn, O, S., Fiala, ES, Puz, C., Hamilton, S. R, and Williams, GM: Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosomethylamine, Cancer Res , 47, 3123-3129,1987] and Tu and Yang Tu, YY, and Yang, CS: High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting. Cancer Res . 43, 623-629, 1983], the amount of formaldehyde produced from N-nitrosodimethylamine was measured by ultraviolet absorption photometry. The culture mixture was NADPH-producing system (3.5 mM glucose glucose-6-phosphate, 1.5 mM NADP, 5 units of glucose-6-phosphate dehydrogenating agent and 3.5 mM MgCl ₂ ), 1 mM N-nitrosodimethylamine and 0.1 M phosphate buffer. (pH 7.4) made up to 2 mg microsomal protein turbid in 1 ml. The mixture was incubated at 37 ° C. for 10 minutes with shaking, and 0.5 ml of 20% trichloroacetic acid (TCA) was added to terminate the reaction and centrifuged. To 1 ml of TCA supernatant was added 0.4 ml of Nash reagent (38.8 mM acetylacetone, 4 M ammonium acetate dissolved in 0.6% (v / v) acetic acid). Color development at 37 ° C. for 60 minutes and absorbance were measured at 405 nm. Enzyme activity was measured compared to the formaldehyde standard curve.

(iv) erythromycin N-demethylating agent

Erythromycin N-demethylating agent (P450 3A4) activity, except that 4 mM semicarbazide was added to the reaction mixture to capture formaldehyde, the incubation time was increased to 30 minutes and 1 mM erythromycin was used as the substrate. And it was measured by the same method as the N-nitrosodimethylamine N-demethylating agent measuring method.

(v) glutathione S-transferase

Glutathione S-transferase (GST) activity in cytosol is described by Hibig et al., Habig, WH, Pabst, MJ and Jakoby, WB: Glutathion S-Trans ferases: The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 249 (22), 7130-7139, 1974]. The reaction mixture was made with 1 mM GSH and 1 mM 1-chloro-2,4-dinitrobenzene (CDNB) in 2 ml of 0.1 M potassium phosphate buffer (pH 6.5). The reaction was initiated by the addition of 10 μg cytosolic protein and the increase at 340 nm due to the formation of the CDNB-GSH conjugate was recorded for 4 minutes. Activity was calculated using an extinction coefficient of 9.6 mM ⁻¹ cm ⁻¹ . Background activity measured without cytosolic protein was subtracted from each value.

(vi) phenol sulfotransferases

Phenol sulfotransferase (PST) activity is described by Sekura and Jakoby in Sekura, RD and Jakoby, W. B ,: Phenol sulfotransferases. J. Biol. Chem. 254 (13), 5658-5663, 1979] was slightly modified and measured by the colorimetric method. The reaction mixture was made up to 0.4 ml in total to contain 0.25 M sodium phosphate buffer (pH 7.4), 0.25 Mβ-naphthol, 5% (v / v) acetone, 5 mM 2-mercaptoethanol and 0.2 mM PAPS. The reaction is initiated by the addition of cytosolic protein. After incubation at 37 ° C for 30 minutes with shaking, 0.5 ml of methyl blue reagent (250 ml of methylene blue, 50 g of anhydrous sodium sulfate and 10 ml of cH ₂ SO ₄ ) was added to 1 L of distilled water and 3 ml of chloroform to terminate the reaction. I was. The two phases were vigorously mixed by vortex mixing for 20 seconds and centrifuged at 2,000 × g for 10 minutes at 4 ° C. The chloroform layer was transferred to another tube containing 50-100 mg of anhydrous sodium sulfate. Absorbance was measured at 653 nm and β-naphthyl sulfate was used as a standard material.

(vii) protein measurement

Proteins were prepared using Low Serum Albumin (BSA) as a standard, Lowry et al., Lowry, OH, Rosebrough, NJ, Farr, AL and Randall, R. T: Protein measurment with the folin phenol reagent. J. Biol. Chem. 193. 265-275, 1951].

result

(1) Effect of Leucocyanidins on Phase I Metabolic Enzymes

Hepatic microsomal fractions of rats orally administered with LC at 50, 100 mg / kg dose for 7 days were isolated and observed for changes in activity of the chitochrome P450 enzymes, as shown in FIGS. 2, 3 and 4. Likewise, the P450 1A1, 1A2, 2B1 activity was significantly reduced to 55.7%, 44.5% and 56.1%, respectively, in the 100 mg / kg administration group. In the 50 mg / kg administration group, the activity of P450 1A1 and 2B1 decreased slightly, but there was no statistical significance.

As shown in FIGS. 5 and 6, another chitochrome P450 enzyme, P450 3A4, was reduced to 84.0% and 77.9% of the normal group in the 50 and 100 mg / kg administration groups. Did not give.

As can be seen in Figure 7, there was no change in the total amount of chitochrome P450, which means that the enzyme activity itself is affected by LC administration.

(2) Effect on phase II metabolic enzyme

As shown in FIGS. 8 and 9, the activity of the enzymatic reaction associated with the phase II metabolic enzyme was measured on the rat microsomes pretreated orally with LC at 50, 100 mg / kg for 7 days. , GST activity was significantly increased to 111.9% and 117.3% of the normal control, respectively, PST also increased to 118.0% in the 100 mg / kg administration group.

Leucocyanidin significantly inhibits the activity of chitochrome P450 1A2, an enzyme that produces the toxic body of acetaminophen, and increases the activity of the Phase II metabolic enzymes GST and PST, which help to be excreted in a short time. It was confirmed to represent. In addition, leucocyanidine has a toxicity inhibitory (mitigating) effect on not only acetaminophen but also all other substances metabolized by chitochrome P450, 1A1, 1A2, 2B1, and 3A4 shown in Table 4 below and exhibiting toxicity. Among all metabolizing enzymes, PST, GST, etc. can be expected to suppress the toxicity (reduction) effect also for the excretion speed is faster.

Main Human Body Chitochrome P450 Enzyme P450 drug Carcinogen / Toxic Substance / Endogenous Substrate 1A1 Berukast (very few drugs) Benzo (a) pyrene, dimethylbena (a) anthracene 1A2 Phenacetin, theophylline, acetaminophen, warfarin, caffeine, cimetidine Aromal Amine, Aritdrocarbon, NNK, Aflatoxin, Estradiol 2A6 Coumarin, Nicotine Aflatoxin, diethylnitrosamine, NNK 2B6 Cyclophosphamide, phosphamide, nicotine 6 Aminocriscene, Aflatoxin, NNK 2C8 Taxol, Tolbutamide, Carbazepine 2C9 Thienic acid, tolbutamide, warfarin, phenytoin, THC, hexobarbital, diclofenac 2C19 S-mefenitoin, diazepam, phenytoin, omeprazole, indomethacin, impramine, propanolol, proguanil 2D6 Debrisosequine, spartane, bufuralol, propanolol, thiolidazine, quinidine, phenytoin, fluoxetine, and many other drugs 2E1 Chloroxazone, isoniazid, acetaminophen, halotane, enfluan, methoxyflurane Dimethylnitrosamine, benzene, halogenated alkanes (e.g. CCl ₄ ), acrylonitrile, alcohols, aniline, styrene, vinyl chloride 3A4 Nifedipine, ethylmorphine, warfarin, quinidine, taxol, ketoconazole, verapamil, erythromycin, diazepam, and many other drugs Aflatoxin, 1-nitropyrene, benzo (a) pyrene, 7,8-diol, 6 aminocrisene, estradiol, progesterone, testosterone, other steroids, bile acids 4A9 / 11 Very few drugs Fatty acids, prostaglandins, thromboxanes, prostacyclins

Although the above has been described the present invention based on the specific embodiments, these are only for illustrative purposes, the present invention will be apparent to those skilled in the art that various changes and modifications within the scope of the invention as defined by the claims. .

Claims (6)

A pharmaceutical composition for protecting liver, comprising an effective amount of leucocyanidin and a pharmaceutically acceptable carrier for inhibiting liver damage. The pharmaceutical composition according to claim 1, for inhibiting liver toxicity by acetaminophen. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for inhibiting hepatotoxicity by a hepatotoxic substance metabolized to a toxic body by a phase I metabolic enzyme. The pharmaceutical composition of claim 3, wherein the phase I metabolic enzyme is P450 1A1, 1A2, 2B1, 3A4, or 2E1. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for inhibiting hepatotoxicity caused by hepatotoxic substances whose excretion rate is accelerated by phase II metabolic enzymes. 6. The pharmaceutical composition of claim 5, wherein the phase II metabolic enzyme is phenol sulfotransferase (PST) and glutathione S-transferase (GST).