CYPIIE1与GSTP1多态性及mRNA水平在酒精性肝病中的研究
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摘要
过度饮酒会导致身体,心理和社会等一系列问题,酒精滥用和依赖是酒精性肝病发病机制中的主要因素,但并不是所有饮酒者均发展为酒精性肝病。细胞色素P450IIE1(CYPIIE1),是存在于肝细胞内的I相物质代谢酶,是微粒体乙醇氧化系统的主要组成部分。谷胱甘肽S-转移酶(GSTP1),是II相物质代谢酶,为重要的外源性化学物质代谢酶,主要催化外源代谢产物的亲电子中心与还原性谷胱甘肽的轭和反应,从而降低外源化合物或(和)致癌化合物的毒性和致癌性。有毒或致癌化合物在肝脏的代谢方向取决于两个酶系统的水平和相互作用。这就提出了一个可能性,即I相物质代谢酶活性增加,同时伴II相物质代谢酶活性减低,可能会使有毒或致癌中间产物增加而导致个体对某些疾病的易感性增加,如酒精性肝病。
本实验抽取自2006年9月至2007年11月,收集来自黑龙江,吉林,辽宁和内蒙古省几家大医院患者的外周血2ml。患者来自汉族,蒙古族,朝鲜族三个民族,其中包括汉族酒精性肝病患者126人;蒙古族酒精性肝病患者118人;朝鲜族酒精性肝病患者109人。各民族饮酒无肝病患者各100人,各民族健康对照者各120人。实时聚合酶链反应(RT-PCR)用于检测CYPIIE1及GSTP1在每组中的基因多态性分布;聚合酶链反应限制性片段长度多态性(PCR-RFLP)用于检测CYPIIE1及GSTP1在酒精性肝病患者及健康对照人群中mRNA的表达水平。结果发现不论何种民族,携带了CYPIIE1 C2和GSTP1 Val等位基因的患者具有酒精性肝病的遗传易感性。C2和Val的分布频率在汉族酒精性肝病患者中分别为50.00%和26.98%;在蒙古族患者中分别为31.36%和22.87%;在朝鲜族患者中分别为45.87%和22.02%,各民族酒精性肝病患者中C2和Val的分布频率无统计学差别(P>0.05)。而在三个民族中,酒精性肝病患者的C2和Val分布频率均显著高于饮酒无肝病者及健康对照者,且具有统计学差别(P<0.05)。不论何种民族,酒精性肝病患者与健康对照者相比均具有较高的CYPIIE1mRNA表达水平,和较低的GSTP1mRNA表达水平,并具有显著的统计学意义(P<0.001)
在本研究中,我们看到:不论何种民族,同时携带CYPIIE1 C2和GSTP1 Val等位基因的人群致使体内CYPIIE1mRNA表达水平上调,GSTP1mRNA表达水平下降而儸患酒精性肝病的的几率明显高于单独携带或不携带CYPIIE1 C2或GSTP1 Val基因的人群。
BACKGROUND: Excessive alcohol intake can cause physical, psychological, and social problems. Alcohol abuse and dependence are major factors in the pathogenesis of alcoholic liver disease (ALD). Not all drinkers develop ALD. Approximately 20% of chronic alcoholics develop hepatic cirrhosis, while 20% tolerate the chronic toxic effects without developing any liver pathology.
Cytochrome P450IIE1 (CYPIIE1), a member of the phase I family of detoxifying liver enzymes, is the main component of the microsomal ethanol oxidizing system. It plays a major role in the metabolic activation of environmental xenobiotics such as ethanol, benzene, and small-molecular-weight procarcinogens, including nitrosamines, or drugs such as acetaminophen, chlorzoxazone, and salicylate. This metabolic activation can give rise to carcinogenic intermediate compounds. However, phase II enzymes, primarily the glutathione S-transferases (GST), normally act on these electrophilic, toxic intermediates by conjugating them to reduced glutathione to produce less toxic or readily excretable metabolites.
The level and persistence of bioactivated toxic or carcinogenic compounds in the liver thus depends on the interplay of both biotransforming enzyme systems. This raises the possibility that an increase in the activity of the phase I system, coupled with a decrease in phase II activity, might increase the level of toxic or carcinogenic intermediates and predispose an individual to developing diseases such as ALD.
A likely contributor to such a potential imbalance between phase I and II enzymes is allelic variation in the genes that encode them. The genes encoding both CYPIIE1 and GSTP1 exist in multiple polymorphic forms, causing their expression level to vary widely among individuals.[6] CYPIIE1 is located on 10q2403-qter. It is 1104 kb gene, consisting of 9 exons and 8 introns, that encodes a 493 amino acid protein. CYPIIE1 contains six restriction fragment length polymorphisms (RFLP), of which the PstI/RsaI polymorphism in its 5’-flanking region, has been shown to affect its transcription level. The C2 allele can enhance the transcription and increases the level of CYPIIE1 enzymatic activity. Similarly, polymorphisms of the GSTP1 gene exist, and were first reported by Board and his colleagues. These consist of an A-to-G transition of nucleotide 313 in exon 5 (GSTP1*B) and a G-to-T transition of nucleotide 341 in exon 6 (GSTP1*C), leading to the substitution of two amino acids in the enzyme active site, Ile to Val and Val to Ala. These allele variants appear to reduce GSTP1 activity, potentially leading to genetic damage and increased cancer risk.
Alcohol abuse is becoming an increasingly severe problem among the Han, Mongol, and Chaoxian nationalities in the northeast of China. The present study was conceived to determine whether variation in the relative frequencies of these polymorphisms might be correlated with the incidence of ALD in patients of these three nationalities.
Methods: Patients were admitted to the study, between September 2006 and November 2007, from several large hospitals in Heilongjiang, Jilin, Liaoning and Neimenggu provinces. Patients were from the Han, Mongol, and Chaoxian nationalities and included, respectively, 126, 118, and 109 adults with ALD. Also included in the study were 100 patients of each nationality who were alcohol dependent without ALD (alcoholic), and 120 healthy people of each nationality as controls .
Real-time polymerase chain reaction (RT-PCR) and PCR restriction fragment length polymorphism (PCR-RFLP) was used in this research.
Results: The respective frequencies of the CYPIIE1 C2 and GSTP1 Val alleles in patients with ALD were: 50.00% and 26.98% in Han patients (Table 2); 31.36% and 22.87% in the Mongol group (Table 3); and 45.87% and 22.02% in the Chaoxian (Table 4). In contrast, the corresponding frequencies in control patients were 10.00% and 8.3% in the Han, 7.50% and 10.00% in the Mongol group, and 11.67% and 9.17% in the Chaoxian. These data revealed an increased frequency of the C2/C2 and Val/Val genotype in ALD patients, as compared to either controls or alcoholics. In each of the three nationalities, the frequency of the C2 allele was significantly higher in the ALD group than in either of the other two groups. The frequency of the C2 allele across all three nationalities included in our study was approximately 35%, which is in agreement with the frequency reported for other Asian populations. The frequency of the C2 and Val alleles did not differ among ALD patients in the three nationality groups. In contrast, for each nationality, the frequency of C2 and Val was higher in ALD patients than in controls.
The average CYPIIE1 mRNA level was higher in ALD patients (10.05%) than in controls (2.21%) (P<0.001). In contrast, GSTP1 mRNA levels were lower in ALD patients (0.53%) than in controls (2.12%) (P<0.001).
Discussion: We found that the relative frequencies of the two CYPIIE1 polymorphic alleles in ALD patients were similar in the three nationalities we studied. The relative frequency of the two GSTP1 alleles was also similar in ALD of all three nationalities, although there is little published data to which these can be compared. However, in each nationality, there was a clear and significant difference in the mRNA levels of CYPIIE1 GSTP1 between ALD patients and controls. Although the genetic and pathophysiological factors that lead to the development of ALD have not been definitively established, we believe the findings we have reported here provide a strong indication that polymorphisms in the genes encoding CYPIIE1 and GSTP1 may contribute significantly to these processes. Our findings indicate that individuals who are homozygous for the CYPIIE1 C2 and GSTP1 Val alleles have higher and lower expression, respectively, of the corresponding enzymes, and appear to have an increased incidence of ALD.
Besides, through our experiment we found that no matter what stages have the ALD developed, the rule of polymorphisms of CYPIIE1 and GSTP1 and the m-RNA expression of the two enzymes are that individuals who are homozygous for the CYPIIE1 C2 and GSTP1 Val alleles have higher and lower expression, respectively. That is to say, there is no difference about polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes among hepatic adipose infiltration, alcoholic hepatitis, and alcoholic cirrhosis. The difference about polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes decides whether it is possible that someone who sufferes from ALD or not, and is nothing with what stages of ALD.
The Han, Mongol, and Chaoxian are nationalities which are good at drinking in north-east of China. So we extensively collected the drinkers from the three nationalities to study the relation between the polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes and ALD in order to discover the pathogeny of ALD, and the rule of morbidity among different races further. Providing the foundation of molecular biology to prophylaxis. Doing some help to treatment about ALD in clinic.
本实验抽取自2006年9月至2007年11月,收集来自黑龙江,吉林,辽宁和内蒙古省几家大医院患者的外周血2ml。患者来自汉族,蒙古族,朝鲜族三个民族,其中包括汉族酒精性肝病患者126人;蒙古族酒精性肝病患者118人;朝鲜族酒精性肝病患者109人。各民族饮酒无肝病患者各100人,各民族健康对照者各120人。实时聚合酶链反应(RT-PCR)用于检测CYPIIE1及GSTP1在每组中的基因多态性分布;聚合酶链反应限制性片段长度多态性(PCR-RFLP)用于检测CYPIIE1及GSTP1在酒精性肝病患者及健康对照人群中mRNA的表达水平。结果发现不论何种民族,携带了CYPIIE1 C2和GSTP1 Val等位基因的患者具有酒精性肝病的遗传易感性。C2和Val的分布频率在汉族酒精性肝病患者中分别为50.00%和26.98%;在蒙古族患者中分别为31.36%和22.87%;在朝鲜族患者中分别为45.87%和22.02%,各民族酒精性肝病患者中C2和Val的分布频率无统计学差别(P>0.05)。而在三个民族中,酒精性肝病患者的C2和Val分布频率均显著高于饮酒无肝病者及健康对照者,且具有统计学差别(P<0.05)。不论何种民族,酒精性肝病患者与健康对照者相比均具有较高的CYPIIE1mRNA表达水平,和较低的GSTP1mRNA表达水平,并具有显著的统计学意义(P<0.001)
在本研究中,我们看到:不论何种民族,同时携带CYPIIE1 C2和GSTP1 Val等位基因的人群致使体内CYPIIE1mRNA表达水平上调,GSTP1mRNA表达水平下降而儸患酒精性肝病的的几率明显高于单独携带或不携带CYPIIE1 C2或GSTP1 Val基因的人群。
BACKGROUND: Excessive alcohol intake can cause physical, psychological, and social problems. Alcohol abuse and dependence are major factors in the pathogenesis of alcoholic liver disease (ALD). Not all drinkers develop ALD. Approximately 20% of chronic alcoholics develop hepatic cirrhosis, while 20% tolerate the chronic toxic effects without developing any liver pathology.
Cytochrome P450IIE1 (CYPIIE1), a member of the phase I family of detoxifying liver enzymes, is the main component of the microsomal ethanol oxidizing system. It plays a major role in the metabolic activation of environmental xenobiotics such as ethanol, benzene, and small-molecular-weight procarcinogens, including nitrosamines, or drugs such as acetaminophen, chlorzoxazone, and salicylate. This metabolic activation can give rise to carcinogenic intermediate compounds. However, phase II enzymes, primarily the glutathione S-transferases (GST), normally act on these electrophilic, toxic intermediates by conjugating them to reduced glutathione to produce less toxic or readily excretable metabolites.
The level and persistence of bioactivated toxic or carcinogenic compounds in the liver thus depends on the interplay of both biotransforming enzyme systems. This raises the possibility that an increase in the activity of the phase I system, coupled with a decrease in phase II activity, might increase the level of toxic or carcinogenic intermediates and predispose an individual to developing diseases such as ALD.
A likely contributor to such a potential imbalance between phase I and II enzymes is allelic variation in the genes that encode them. The genes encoding both CYPIIE1 and GSTP1 exist in multiple polymorphic forms, causing their expression level to vary widely among individuals.[6] CYPIIE1 is located on 10q2403-qter. It is 1104 kb gene, consisting of 9 exons and 8 introns, that encodes a 493 amino acid protein. CYPIIE1 contains six restriction fragment length polymorphisms (RFLP), of which the PstI/RsaI polymorphism in its 5’-flanking region, has been shown to affect its transcription level. The C2 allele can enhance the transcription and increases the level of CYPIIE1 enzymatic activity. Similarly, polymorphisms of the GSTP1 gene exist, and were first reported by Board and his colleagues. These consist of an A-to-G transition of nucleotide 313 in exon 5 (GSTP1*B) and a G-to-T transition of nucleotide 341 in exon 6 (GSTP1*C), leading to the substitution of two amino acids in the enzyme active site, Ile to Val and Val to Ala. These allele variants appear to reduce GSTP1 activity, potentially leading to genetic damage and increased cancer risk.
Alcohol abuse is becoming an increasingly severe problem among the Han, Mongol, and Chaoxian nationalities in the northeast of China. The present study was conceived to determine whether variation in the relative frequencies of these polymorphisms might be correlated with the incidence of ALD in patients of these three nationalities.
Methods: Patients were admitted to the study, between September 2006 and November 2007, from several large hospitals in Heilongjiang, Jilin, Liaoning and Neimenggu provinces. Patients were from the Han, Mongol, and Chaoxian nationalities and included, respectively, 126, 118, and 109 adults with ALD. Also included in the study were 100 patients of each nationality who were alcohol dependent without ALD (alcoholic), and 120 healthy people of each nationality as controls .
Real-time polymerase chain reaction (RT-PCR) and PCR restriction fragment length polymorphism (PCR-RFLP) was used in this research.
Results: The respective frequencies of the CYPIIE1 C2 and GSTP1 Val alleles in patients with ALD were: 50.00% and 26.98% in Han patients (Table 2); 31.36% and 22.87% in the Mongol group (Table 3); and 45.87% and 22.02% in the Chaoxian (Table 4). In contrast, the corresponding frequencies in control patients were 10.00% and 8.3% in the Han, 7.50% and 10.00% in the Mongol group, and 11.67% and 9.17% in the Chaoxian. These data revealed an increased frequency of the C2/C2 and Val/Val genotype in ALD patients, as compared to either controls or alcoholics. In each of the three nationalities, the frequency of the C2 allele was significantly higher in the ALD group than in either of the other two groups. The frequency of the C2 allele across all three nationalities included in our study was approximately 35%, which is in agreement with the frequency reported for other Asian populations. The frequency of the C2 and Val alleles did not differ among ALD patients in the three nationality groups. In contrast, for each nationality, the frequency of C2 and Val was higher in ALD patients than in controls.
The average CYPIIE1 mRNA level was higher in ALD patients (10.05%) than in controls (2.21%) (P<0.001). In contrast, GSTP1 mRNA levels were lower in ALD patients (0.53%) than in controls (2.12%) (P<0.001).
Discussion: We found that the relative frequencies of the two CYPIIE1 polymorphic alleles in ALD patients were similar in the three nationalities we studied. The relative frequency of the two GSTP1 alleles was also similar in ALD of all three nationalities, although there is little published data to which these can be compared. However, in each nationality, there was a clear and significant difference in the mRNA levels of CYPIIE1 GSTP1 between ALD patients and controls. Although the genetic and pathophysiological factors that lead to the development of ALD have not been definitively established, we believe the findings we have reported here provide a strong indication that polymorphisms in the genes encoding CYPIIE1 and GSTP1 may contribute significantly to these processes. Our findings indicate that individuals who are homozygous for the CYPIIE1 C2 and GSTP1 Val alleles have higher and lower expression, respectively, of the corresponding enzymes, and appear to have an increased incidence of ALD.
Besides, through our experiment we found that no matter what stages have the ALD developed, the rule of polymorphisms of CYPIIE1 and GSTP1 and the m-RNA expression of the two enzymes are that individuals who are homozygous for the CYPIIE1 C2 and GSTP1 Val alleles have higher and lower expression, respectively. That is to say, there is no difference about polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes among hepatic adipose infiltration, alcoholic hepatitis, and alcoholic cirrhosis. The difference about polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes decides whether it is possible that someone who sufferes from ALD or not, and is nothing with what stages of ALD.
The Han, Mongol, and Chaoxian are nationalities which are good at drinking in north-east of China. So we extensively collected the drinkers from the three nationalities to study the relation between the polymorphisms of CYPIIE1、GSTP1 and the m-RNA expression of the two enzymes and ALD in order to discover the pathogeny of ALD, and the rule of morbidity among different races further. Providing the foundation of molecular biology to prophylaxis. Doing some help to treatment about ALD in clinic.
引文
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