CN1195522A - Use of 2(3) tertiary butyl-4-hydroxy-anisole in preparation of drug for preventing and curing tissue organ traumatic disease - Google Patents

Abstract

The present invention relates to a new compound BHA (2(3)tert-butyl-4-hydroxyanisole) and its application in preparation of medicine for preventing and curing traumatic diseases of tissue and organs of mammals including human. Taking BHA can obviously raise several antioxidases and antioxidant substances in human body, enhance function of eliminating internal free radical and reduce the production of lipid peroxide. The BHA possesses obvious protection action for experimental injury of mouse liver and myocardium and rat's gastric mucosa, and possesses the obvious effect for inhibiting hepatic tumor nodule formation of HBsAg transgenic mouse. The BHA can be used as a medicine for resisting oxidation, resisting injury, resisting senility and resisting tumor, so that it possesses the good functions for preventing and curing several diseases of human body.

Description

2 (3) tertiary butyl-4-hydroxy methoxybenzene are prevented and treated application in the injuries of tissues and organs disease medicament in preparation

The present invention relates to chemical compound 2 (3) tertiary butyl-4-hydroxy methoxybenzene (being called for short BHA) and prevent and treat the application of injuries of tissues and organs disease medicament as preparation; particularly be applied to hepatitis, myocardial damage, gastric mucosal lesion that various factors causes; and chemotherapeutics and other had the protection and the detoxifcation aspect of toxicity, side effect material to body, the control that also is applied to tumor especially is especially to the control of hepatocarcinoma with to the defying age aspect of body.

Compd B HA full name is 2 (3)-tert-butyl-4-hydroxyanisole, comprise 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole or its five equilibrium mixture of isomers, or exist with its sodium salt and other acceptable salt form, Chinese is: 2 (3) tertiary butyl-4-hydroxy methoxybenzene, molecular formula are C ₁₁H ₁₆O ₂, molecular weight 180.24.Structural formula is:

BHA is a compound known, and before its main uses was to be used for food and edible oil (content is equivalent to 2mg/ days/people) as antioxidant and antiseptic.Its preparation method is seen United States Patent (USP) 2459540 and 2470902, and relevant document also has: European Patent Application No. 84111784.9 (publication number 0141275A1), PCT WO publication number 88/07856 etc.According to relevant bibliographical information, BHA not only has stronger antioxygenic property, and little very little for the toxicity of human body and animal.The India Rhesus Macacus is taken 500mg/kg every day, takes one month, and food Eriocheir sinensis macaque 400mg/kg every day took three months, and beagle 220mg/kg every day takes and there is no toxic performance in six months.According to the disclosure document 0141275A1 report of european patent application, BHA is added in the food with vitamin C, selenium etc. as one of anti-cancer group thing component has synergism to cancer prevention.Document WO 88/07856 is mentioned BHA and be can be used as medication preparation and be used to prevent and treat acquired immune deficiency syndrome (AIDS) and diseases related, and its mechanism of action is that BHA has disturbed the infectivity of retrovirus to body cell.

The antioxidant material of present clinical use also can not satisfy clinical needs far away, and as vitamin preparations such as vitamin E vitamin Cs, because of it is the needed by human composition, its pharmacological action is still waiting certainly; Also have some antioxidant reductases such as superoxide dismutase, at room temperature unstable because of it, need under specific condition, preserve, and in vivo the half-life very short, the SOD plasma half-life is only 5-20 minute in animal body, thereby is difficult to bring into play its pharmacological action in vivo; Other antioxidant such as reduced glutathion (commodity are called Tai Te) etc. also exist the problems such as limitation of clinical practice.

The inventor finds uncannily, by the antioxidation of bringing into play of inducing of BHA pair cell protective enzyme, and can be as the application in the medicine of preparation prevention and treatment human tissue organ injury disease.

The objective of the invention is to find the new purposes of compd B HA; be that BHA is by improving multiple antioxidase and antioxidant such as quinone reductase in the body; glutathione S-transferase; glutathion reductase; reduced glutathione etc.; prevent and treat application in the medicine of injuries of tissues and organs disease in preparation; particularly be applied to the hepatitis that various factors causes; myocardial damage; gastric mucosal lesion; and it is poisonous to body to chemotherapeutics and other; the protection of side effect material and detoxifcation aspect, the control that also is applied to tumor especially are especially to the control of hepatocarcinoma with to the defying age aspect of body.

Main design of the present invention is, present known free radical is relevant with the morbidity of numerous disease, these diseases comprise generation of hepatic injury, AGML, coronary heart disease, poisoning, occupation disease, infectious disease and cell mutation and tumor or the like, and the infringement of free radical also is one of important factor in old and feeble mechanism.Under normal circumstances, body has perfect anti-oxidative defense system, comprise various antioxidases such as superoxide dismutase (superoxide dismutase, SOD), glutathione S-transferase (Glutathion-S-Transferases, GSTs), glutathion reductase (Glutathion Reductase, GR) and quinone reductase (Quinone Reductase, and antioxidant such as reduced glutathione (GSH) etc. QR) etc., the free radical that body is produced maintains under the normal physiological status, does not cause tissue injury.But under various pathological conditions, or the generation free radical increases in the body, or the anti-oxidative defense ability drop of body, and free radical is just accumulated in vivo, and produces lipid peroxide, finally causes tissue injury.One of its feature of quinone reductase is exactly can the catalysis quinones substance to carry out two electron reductions and forms stable hydroquinone, thereby has blocked the generation of semiquinone free radical; SOD has the effect of direct removing superoxide anion; Glutathione then can (destruction SH) be and in antioxidase coordinating protection cell membrane such as GSTs and GR-protein and the enzyme of SH and containing-SH do not destroy by free radical or other oxidant to antioxidant and radical pair sulfydryl.The present invention shows: when taking BHA, multiple antioxidase and antioxidant can significantly increase in the body, and can significantly reduce the generation of lipid peroxide.In zoopery, 0.5%BHA is stirred in (W/W in the mash feed, unless specified otherwise, as follows) took 3 days to mice, its serum quinone reductase (QR) of comparing with the matched group of not giving BHA significantly improves (P＜0.0001), QR, glutathione S-transferase (GSTs), the equal significance of glutathion reductase (GR) increase (P＜0.0001) in liver tissue homogenate's liquid, see Table 1.Can increase QR and GST activity (P＜0.0001 and P＜0.01) equally to mouse cardiac muscle, see Table 2.Rat was taken 0.5%BHA3 days, also significantly induces gastric mucosa of rat QR activity (P＜0.001), and can significantly reduce gastric mucosa of rat the lipid peroxidation product malonaldehyde (Malonaldehyde, MDA) content (P＜0.01) sees Table 3; Give mice 0.5%BHA2 month, the inventor finds that also BHA can significantly increase reduced glutathion in the liver organization (GSH) content (P＜0.01); See Table 4.And, see that its removing ability of Fig. 1 is 579.5 times of mannitol in the generation (P＜0.01) that external 0.6 μ M BHA can significantly remove hydroxy radical.

Table 1 BHA is to mice serum and the active inducing action of hepatic antioxidant

Serum (U/L) liver homogenate liquid (nmol/min/mg albumen)

QR QR GST-CDNB ^§GR normal control group 54.5 ± 9.55 78.1 ± 15.8 5803 ± 1,604 47.2 ± 5.070.5%BHA group 92.3 ± 10.4****, 500 ± 82.7****, 13281 ± 3162***, 88.1 ± 8.72**** and normal control group compare: * * * P＜0.001; * * * P＜0.0001 ^§(1-chloro-2,4-dinitrobenzene CDNB) measure the GST activity for substrate with 1-chloro-2,4 dinitro benzenes.

Table 2 BHA organizes the active inducing action of QR, GST to mouse cardiac muscle

Cardiac muscle homogenate (nmol/min/mg albumen)

QR GST-CDNB normal control group 433 ± 16.8 87.9 ± 7.510.5%BHA group 505 ± 21.1****, 104 ± 6.04** and normal control group compare: * * P＜0.01; * * * P＜0.0001

Table 3 BHA is to the lipid antioxidation of gastric mucosa of rat

The gastric mucosa homogenate

MDA (nmol/mg albumen) QR (nmol/min/mg albumen) normal control group 5.20 ± 0.877 1472 ± 1790.5%BHA group 3.00 ± 0.379**, 2009 ± 203*** and normal control group compare: * * P＜0.01; * * P＜0.001

Table 4 BHA is to the influence of mouse liver tissue GSH content

GSH (μ mol/g hepatic tissue) P value

Normal control group 4.55 ± 0.33

0.5%BHA group 9.97 ± 0.65＜0.01

In addition, the inventor finds that also BHA is nontoxic for body basically in range of doses.Measure the LD of BHA mice with the improvement karber's method ₅₀(median lethal dose(LD 50)) is 1418.3mg/kg, its 95% average credible 1328.8mg/kg～1507.8mg/kg that is limited to; Give the long-term nursing of mice 0.5%BHA 18～24 months, do not see that with matched group mice body weight and serum GPT have significant change (P＞0.05), see Table 5; Give mouse stomach heavy dose of BHA 800mg/kg/ days (near median lethal dose(LD 50)), connect and give 3 days, the result does not find that body important organ such as liver, cardiac muscle etc. have significant change, and sees Table 6, illustrates that body is fabulous to the toleration of compd B HA.According to above-mentioned research; compd B HA has the effect of inducing cell protective enzyme QR, GSTs and GR, and can increase the antioxidant of body such as the content of GSH, reduces the generation of lipid peroxide MDA simultaneously; and its toxicity is minimum, and this just provides pharmacological basis for clinical practice.The inventor uses compd B HA has carried out a series of preventive and therapeutic effect on the multiple animal model relevant with human diseases research in view of the above.

Table 5 is taken BHA for a long time and mice body weight and glutamate pyruvate transaminase (GPT) is not exerted an influence

Mice body weight (g) serum GPT (U/L)

General matched group 31.1 ± 6.31 22.9 ± 10.9 of raising

0.5%BHA group 29.8 ± 0.994 ^@17.7 ± 8.31 ^@

Compare with the general matched group of raising: ^@P＞0.05

The heavy dose of BHA of table 6 is to mouse liver, cardiac muscular tissue's non-invasi effect

Serum (U/L)

GPT GOT ^#LDH ^CPK ^γThe heavy dose of BHA group 24.5 ± 16.1 in normal control group 19.7 ± 8.24 28.9 ± 15.5 75.7 ± 20.5 63.0 ± 22.4 ^@39.6 ± 16.7 ^@87.3 ± 24.9 ^@77.5 ± 44.4 ^@Compare with the normal control group: ^@P＞0.05 ^#Glutamic oxaloacetic transaminase, GOT; The ^ lactic acid dehydrogenase; ^γCreatine phosphokinase

The present invention has four accompanying drawings:

Figure 1B HA is in external direct scavenging action to hydroxy radical.

Fig. 2 various dose BHA brings out the protective effect of liver, myocardial toxicity to amycin;

Fig. 3 BHA is the growth inhibited effect of BGC-823 to stomach cancer cell;

Fig. 4 BHA+ chemotherapeutics is to the growth inhibited effect of hepatoma cell line BEL-7402;

Fig. 5 BHA+ chemotherapeutics is to the growth inhibited effect of colon carcinoma cell line HCT.

Provide 11 routine embodiment below in conjunction with accompanying drawing and table 7-table 15.Embodiment 1 compd B HA brings out the preventive and therapeutic effect of mouse liver injury to carbon tetrachloride

Give mice 0.5%BHA and 1% compound vitamin (including VitC, VitE, compound vitamin B, VitA and VitD etc.) 2 months, give the single dose carbon tetrachloride more respectively, BHA group serum GPT significantly reduces (P＜0.0001) than matched group (single carbon tetrachloride of giving) as a result; Medication BHA group also significantly reduces (P＜0.0001) than compound vitamin group serum GPT; Anti-oxidative damage index BHA groups such as the liquid QR of liver tissue homogenate, GSTs, SOD, GSH all are significantly higher than matched group and vitamin group simultaneously, see Table 7.

Table 7 BHA is to CCl ₄Bring out toxic protective effect of mouse liver and mechanism

The serum liver homogenate

GPT QR GST-CDNB SOD GSH MDA

(U/L) (nmol/min/mg albumen) (nmol/min/mg albumen) (NU/mg albumen) (μ mol/g hepatic tissue) (nmol/mg albumen) CCl ₄Group 220 ± 31.8 95.0 ± 14.0 4760 ± 452 34.4 ± 4.80 3.73 ± 0.320 4.34 ± 0.476BHA+CCl ₄Group 70.2 ± 21.7**** ^##577 ± 95.5**** ^##10346 ± 835**** ^##47.9 ± 6.96** ^#8.75 ± 1.07**** ^##3.30 ± 0.416** compound vitamin+CCl ₄Group 175 ± 37.0*, 140 ± 18.9***, 3475 ± 354 38.4 ± 5.0 4.75 ± 0.394**, 3.56 ± 0.464** and CCl ₄Group compares: * P＜0.05; * P＜0.01; * * P＜0.001; Compare with compound vitamin * * * P＜0.0001: ^#P＜0.05: ^##P＜0.0001

Embodiment 2 compd B HA Abensanils bring out the preventive and therapeutic effect of mouse liver injury

Give mice 0.5%BHA2 week; give the single dose acetaminophen again; BHA group serum GPT significantly reduces (P＜0.0001) than matched group (single to the acetaminophen group) as a result; liver MDA content also significantly reduces (P＜0.0001) than matched group; protectiveness index BHA such as the liquid QR of liver tissue homogenate, GSTs, SOD and GSH group all is significantly higher than matched group (P＜0.0001 or P＜0.01), sees Table 8.

Table 8 BHA Abensanil brings out toxic protective effect of mouse liver and mechanism

The serum liver homogenate

GPT QR GST-CDNB SOD GSH MDA

(U/L), (nmol/min/mg albumen), (nmol/min/mg albumen), (NU/mg albumen), (μ mol/g hepatic tissue), (nmol/mg albumen) acetaminophen group 482 ± 140 109 ± 20.7 1212 ± 207 10.5 ± 1. 5.31 ± 1.18 5.90 ± 0.727BHA+ acetaminophen groups, 11.9 ± 3.38****, 733 ± 58.3****, 8970 ± 942****, 13.5 ± 1.20****, 8.74 ± 0.82****, 4.08 ± 0.732**** and acetaminophen group compare: * * * * P＜0.0001

Embodiment 3 compd B HA bring out the preventive and therapeutic effect of hepatic injury to the chemotherapeutics amycin

Give mice 0.5%BHA totally 5 days, the back was given amycin 15mg/kg ip, once a day in 2 days, BHA+ amycin group is single to amycin group serum GPT significantly descend (P＜0.01) as a result, liver homogenate liquid MDA content also reduces (P＜0.0001), the active all significances of myocardium antioxidase QR, GSTs and GR increase (P＜0.0001) simultaneously, see Table 9.

Table 9 BHA brings out toxic protective effect of mouse liver and mechanism to amycin

The serum liver homogenate

GPT QR GST-CDNB GR MDA

(U/L) (nmol/min/mg albumen) (nmol/min/mg albumen) (nmol/min/mg albumen) (nmol/mg albumen)

Amycin group 328 ± 103 147 ± 46.4 5060 ± 1,476 47.2 ± 5.44 4.64 ± 0.216

BHA+ amycin group 149 ± 48.8** 783 ± 122**** 5389 ± 3464**** 96.8 ± 7.67**** 3.72 ± 0.231****

Compare with the amycin group: * * P＜0.01; * * * P＜0.0001 embodiment, 4 compd B HA bring out the preventive and therapeutic effect of myocardial damage to the chemotherapeutics amycin

Give mice 0.5%BHA totally 5 days, the back was given amycin 15mg/kg ip in 2 days, once a day, BHA+ amycin group is single as a result significantly reduces (P＜0.0001 and P＜0.001) to amycin group Serum LDH (lactic acid dehydrogenase), CPK (creatine phosphokinase), cardiac muscle homogenate MDA content also significantly reduces (P＜0.01), antioxidase QR of cardiac bistiocyte and GST-CDNB activity significantly increase (P＜0.05) simultaneously, see Table 10.

Table 10 BHA brings out toxic protective effect of mouse cardiac muscle and mechanism to amycin

Serum cardiac muscle homogenate

LDH CPK QR GST-CDNB MDA

(U/L) (U/L) (nmol/min/mg albumen) (nmol/min/mg albumen) (nmol/mg albumen) amycin group 784 ± 145 243 ± 48.8 440 ± 259 92.3 ± 4.88 25.9 ± 2.41BHA+ amycin groups, 358 ± 50.1****, 175 ± 40.1***, 478 ± 27.9*, 104 ± 11.7*, 21.5 ± 2.36** and amycin group are relatively: * P＜0.05; * P＜0.01; * * P＜0.001; * * * P＜0.0001 embodiment, 5 BHA bring out the preventive and therapeutic effect of liver, myocardial damage to dicoumarol+amycin

Dicoumarol has specificity and suppresses the active effect of QR, can significantly increase the toxicity of amycin, after giving mice 0.5%BHA3 days, the liver that BHA brings out dicoumarol+amycin, myocardial damage still have tangible preventive and therapeutic effect, performance GPT decline (P＜0.01), CPK reduces (P＜0.05) and LDH reduces (P＜0.001), sees Table 11.

The liver that table 11 BHA brings out dicoumarol+amycin, the protective effect of myocardial toxicity

Serum (U/L)

GPT CPK LDH dicoumarol+amycin 1351 ± 671 336 ± 76.8 1934 ± 445BHA+ dicoumarol+amycin, 314 ± 133**, 232 ± 35.8*, 792 ± 236*** and dicoumarol+amycin group compares: * P＜0.05; * P＜0.01; * * P＜0.001 embodiment, 6 compd B HA can significantly reduce chemotherapy drugs in combination and use the mortality rate that is caused

Give 3 weeks of mice 0.5%BHA intermittent administration, give cyclophosphamide 400mg/kg/ days totally 4 days during this period, methotrexate 500mg/kg one day, cytosine arabinoside 15mg/kg one day, the result is respectively 40% and 100% with chemotherapeutics group three all backs animal dead rates for BHA+ combined chemotherapy group and list, two group differences are (P＜0.01) significantly, table 12.

Table 12 BHA is to the protective effect of the drug-induced mouse death rate of combined chemotherapy

Animal number three all mortality rate P value cyclophosphamide+methotrexates+cytosine arabinoside 10 100%BHA+ cyclophosphamide+methotrexates+cytosine arabinoside 10 40%＜0.01 embodiment 7 various dose BHA bring out the protective effect of liver, myocardial toxicity to amycin

Adopt BHA 1mg/kg, 7mg/kg, 14mg/kg, 20mg/kg, 25mg/kg, 50mg/kg, 100mg/kg, 200mg/kg, 9 dosage groups such as 400mg/kg are given mouse stomach, once a day, irritate after 3 days, give single dose amycin 30mg/kg, get blood after 24 hours, measure serum GPT, GOT, four indices such as LDH and CPK, found that BHA to mice 7mg/kg dosage, (P is respectively less than 0.05 for all remarkable simultaneously reduction of four indices, 0.01,0.001 and 0.019), it is on a declining curve and maintain the dosage range of broad to increase curve with BHA dosage, as shown in Figure 2, the BHA that 7mg/kg is described promptly demonstrates has remarkable reduction effect simultaneously to four kinds of damaging indexs, and maintains more heavy dose of scope.The preventive and therapeutic effect that embodiment 8 compd B HA form HBsAg transgenic mice liver neoplasm tuberosity

Utilize HBsAg transgenic C ₅₇Mice is at tumorigenic this animal model of certain hour liver energy, when this mice was born back one month, be divided into two groups, give general raising for one group, give feedstuff for one group with 0.5%BHA, continue to feed after 18～24 months, observe the number that mouse liver surface tumor tuberosity forms.The result forms the more general matched group of raising of number to BHA group tumor tuberosity and significantly reduces (P＜0.05), illustrates that BHA has the effect that antitumor forms.

The preventive and therapeutic effect that table 13 BHA forms transgenic mice liver neoplasm tuberosity

Liver tumor tuberosity number (individual) P value

The general matched group 167 ± 11.2 of raising

0.5%BHA group 97.0 ± 33.1＜0.05 embodiment 9 compd B HA are to the preventive and therapeutic effect of alcohol-induced rat pipe film injury

Give after rat 0.5%BHA3 days; irritate stomach for the single dose dehydrated alcohol; BHA+ dehydrated alcohol group can significantly be protected gastric mucosa injury (P＜0.0001) by alcohol-induced with single to the comparison of ethanol group as a result; and gastric mucosa homogenate MDA content decline (P＜0.0001); cell antioxidase QR increases (P＜0.05); and can stop SOD to reduce (P＜0.05), see Table 14.

Table 14 BHA is to the protective effect and the mechanism of alcohol-induced rat pipe film injury

The gastric mucosa homogenate

Damage index QR SOD MDA

(mm) (nmol/min/mg albumen) (NU/mg albumen) (nmol/mg albumen) ethanol group 67.8 ± 16.7 966 ± 122 7.65 ± 0.462 6.55 ± 0.749BHA+ ethanol groups, 17.5 ± 9.18****, 1332 ± 335*, 8.32 ± 0.487*, 3.34 ± 0.264*** and ethanol group are relatively: * P＜0.05; * * P＜0.001; * * * P＜0.0001 embodiment, 10 compd B HA Study of Anti-senility

C ₅₇Male mice is born and promptly was divided into two groups in back one month, one group is stirred in the general middle nursing of raising with 0.5%BHA, and another group is generally fed fosterly with what do not give BHA, continues to feed 18-24 month, put to death mice, measure antioxidase QR, GST and lipid peroxidation product MDA in the liver homogenate liquid.The result is as shown in Table 15, significantly increases (P＜0.0001) to BHA group activities of antioxidant enzymes, and lipid peroxidation product MDA compares with matched group and then significantly reduces (P＜0.01), shows that BHA has remarkable anti-aging effects.

Table 15 compd B HA anti-aging effects

Liver homogenate liquid

MDA QR GST-CDNB

General group 276 ± 55.5 275 ± 60.5 3283 ± 288 general groups 332 ± 29.2 37.7 ± 7.47 1227 ± 158 of raising of raising of (nmol/g hepatic tissue) (nmol/min/mg albumen) (nmol/min/mg albumen) BHA+

P＜0.01＜0.0001＜0.0001 embodiment, 11 compd B HA and with chemotherapeutics in external influence to tumor cell

Experiment shows: BHA promotes the growth effect external itself tumor cell being there is no, on the contrary along with drug level to increase the growth that then demonstrates tumor cell inhibited, as shown in Figure 3, BHA is that the growth of BGC-823 is inhibited to stomach cancer cell when heavy dose, then influences little when low dose of.By Fig. 4, Fig. 5 as can be known, when BHA and chemotherapeutics such as amycin, ametycin during external share, to the growth of hepatoma cell line Bel-7402, BHA is not observed in the growth of colon carcinoma cell line HCT to be had the curative effect of chemotherapeutics and promotes or inhibitory action (P＞0.05).

Find that according to the inventor compd B HA not only has the effect of direct removing hydroxyl free radical; and the more important thing is and to induce multiple antioxidase and antioxidant activity to increase in vivo; as QR; GSTs; GR and reduced glutathione etc.; thereby multiple injuries of tissues and organs disease and anti-aging effects are protected and are treated in performance significantly; this is that the antioxidation preparation of present clinical use (comprises Tai Te; SOD; vitamin; mannitol etc.) can not compare; therefore compd B HA can and bring into play it by the oxidation resistance of enhancing body self and cure the disease and the effect of diseases prevention by direct removing free radical, and its action effect all significantly surpasses mannitol and vitamin.

This invention compd B HA can be used as the patient that effective ingredient is used for above-mentioned prevention and treatment of diseases, and according to the necessary carrier mass of existing pharmaceutical methods adding, excipient, buffer agent etc., can be prepared into various dosage forms to compd B HA, be used for oral, injection and medicine for external use as tablet, capsule, injection, aerosol, lotion, Emulsion, ointment etc.; This invention compd B HA can also be used to be equivalent to the application that this curative effect of medication is a purpose as the composition in any compound medicinal formulation; This invention compd B HA can also be used for the prevention of above-mentioned relevant disease as the active ingredient of health product and improve antioxidation, the defying age ability of body.Dosage range of application of the present invention should be at＞1mg/kg～400mg/kg.

Claims (14)

1, following structural I chemical compound 2 (3) tertiary butyl-4-hydroxy methoxybenzene; 2 (3)-tert-butyl-4-hydroxyanisole; BHA; it is characterized in that comprising application in people's the medicine of injuries of tissues and organs disease as preparation prevention and treatment mammal; particularly be applied to hepatitis, myocardial damage, gastric mucosal lesion that various factors causes; and chemotherapeutics and other had the protection and the detoxifcation aspect of toxicity, side effect material to body, also be applied to the control of tumor and the defying age aspect of body especially.

2, application according to claim 1, the medicinal form of accepting of wherein said BHA is 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole or its five equilibrium mixture of isomers, or its sodium salt and other acceptable salt form.

3, application according to claim 1, wherein said medicine is applicable to hepatitis.

4, application according to claim 1, wherein said medicine is applicable to tumor patient.

5, application according to claim 1, wherein said medicine is applicable to the patient of myocardial damage.

6, application according to claim 1, wherein said medicine are applicable to accepts chemotherapeutics and other have the damage working substance to body patient.

7, application according to claim 1, wherein said medicine is applicable to the patient of gastric mucosa injury.

8, application according to claim 1, wherein said medicine are applicable to contact noxious substance or the patient who wrongly takes poisonous substance.

9, application according to claim 1, wherein said medicine can also be as antiaging agent.

10, application according to claim 1, wherein said medicine can also be used to be equivalent to the application that this curative effect of medication is a purpose as the active ingredient of health product.

11, the composition that application according to claim 1 and 2, wherein said medicine can be used as in any compound medicinal formulation is used to be equivalent to the application that this curative effect of medication is a purpose.

12, application according to claim 1 and 2, wherein said medicine also include necessary carrier mass, excipient, buffer agent etc.

13, that application according to claim 1 and 2, wherein said medicine comprise is oral, injection, and dosage form such as external.

14, application according to claim 1 and 2, wherein said curative effect of medication dosage range is at＞1mg/kg～400mg/kg.

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