王守林
1.新型化学物代谢酶的功能研究;2.环境化学物的生物转化与代谢组学研究;3.药物代谢与药物疗效敏感性及毒副效应研究。
个性化签名
- 姓名:王守林
- 目前身份:
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- 学位:
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学术头衔:
博士生导师
- 职称:-
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学科领域:
细胞生物学
- 研究兴趣:1.新型化学物代谢酶的功能研究;2.环境化学物的生物转化与代谢组学研究;3.药物代谢与药物疗效敏感性及毒副效应研究。
王守林,男,1967年12月生,博士,教授,博士生导师。1991年毕业于南京医科大学并留校任教至今,先后获南京医科大学硕士和博士学位。现任卫生毒理学系副主任、公共卫生学院教工一支部书记、现代毒理学教育部重点实验室办公室副主任等职,是江苏省“333高层次人才培养工程”中青年科学技术带头人、中国毒理学会生殖毒理专业委员会委员、江苏省性学会理事等。1999年2月 ~ 2000年4月,中山大学和National University of Singapore (NUS)访问学者,主要从事细胞和分子毒理学以及人群生殖流行病学研究;2002年10月-11月,美国University of California at Los Angeles (UCLA)从事生殖流行病学的科研学习和交流;2003年4月-2006年3月,美国 University of Medicine and Dentistry of New Jersey (UMDNJ) 从事细胞和分子毒理学研究工作,侧重研究人致癌物代谢酶及其自然变异体的功能,作为主要研究者首次发现人CYP2A13是一种全新高效的代谢活化AFB1的CYP亚型酶,为深入研究AFB1与呼吸系统肿瘤发生的关系提供了崭新的途径。先后主持国家“973”课题、国家“十一五”科技支撑计划(分课题)、国家自然科学基金、国家环保公益基金课题、江苏省自然科学基金、省教育厅和省卫生厅重点项目等科研项目10余项;发表论文100余篇,其中SCI收录文章40余篇;参编教材3部;获江苏省科技进步一等奖(2002)、中华预防医学会科学技术奖三等奖(2007)、常州市科技进步一等奖(2006)各1项,南京医科大学优秀教学成果二等奖1项(2002),获南京医科大学扬子江奖教金优秀奖(2008)和江苏省高校优秀共产党员称号(2008)。
研究方向:
1.新型化学物代谢酶的功能研究
2.环境化学物的生物转化与代谢组学研究
3.药物代谢与药物疗效敏感性及毒副效应研究
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成果数
5
王守林, Shou-Lin Wang, Jing-Fen Han, Xiao-Yang He, Xin-Ru Wang, and Jun-Yan Hong
DRUG METABOLISM AND DISPOSITION Vol. 35, No.1 35: 176-179, 2007,-0001,():
-1年11月30日
The importance of genetic variation in clinical response to various drugs is now well recognized. Identification of genetic biomarkers that can predict efficacy and toxicity of chemotherapeutic drugs in cancer patients holds great promise in treatment improvement and cost reduction. Mitomycin C (MMC) is a common anticancer drug used for the treatment of numerous types of tumors. Metabolismmediated activation, by either one-electron or two-electron reduction, plays a critical role in the chemotherapeutic action of MMC. NADPH-cytochrome P450 (oxido)reductase (POR) is a major enzyme responsible for MMC activation through the one-electron reductive pathway, which leads to the production of semiquinone anion radicals and subsequent DNA damage in the cells. Recently, a total of six naturally occurring human POR variants with single amino acid changes (Y181D, A287P, R457H, V492E, C569Y, and V608F) have been identified. Although the catalytic efficiency of these variants in reduction of cytochrome c was reported to be altered, their capability in activating MMC, a direct substrate of POR, has not been examined. In the present study, we demonstrated that except for the C569Y variant, MMC-induced toxicity assayed as cell viability and proliferative capability was significantly decreased in the Flp-In Chinese hamster ovary cells stably expressing all the other POR variants in comparison with the cells expressing wild-type human POR. Cells expressing the V608F and Y181D variants had a complete loss of the capability to activate MMC. Our finding suggests that these functional POR genetic variations may serve as a potential biomarker to predict the chemotherapeutic response to MMC.
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王守林, Shou-Lin Wang, *, † Xiao-Yang He, * Jian Shen, ‡ Jia-Sheng Wang, § and Jun-Yan Hong*,
TOXICOLOGICAL SCIENCES 94(1), 38-45(2006),-0001,():
-1年11月30日
Cytochrome P450 2A13 (CYP2A13), an enzyme predominantly expressed in human respiratory tissues, is highly efficient for the metabolic activation of two suspected human lung carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and aflatoxin B1 (AFB1). Functional genetic polymorphisms of CYP2A13 may therefore be an important factor in human susceptibility to related lung cancers. Among the reported CYP2A13 polymorphisms with missense variations, only CYP2A13*2 variant (containing either a single or double variation of R25Q and R257C) was studied for its NNK-metabolizing activity. The present study demonstrated that there was no remarkable difference in AFB1-and NNK-induced toxicity between the Flp-In Chinese Hamster Ovary (CHO) cells stably expressing wild-type CYP2A13 and the cells expressing the individual polymorphic variants R25Q, D158E, R257C, R25Q/R257C, V323L, F453Y, and R494C. In contrast, cells transfected with R101Q variant complementary DNA (cDNA), same as the vector control cells, showed no significant death even at highest concentrations of AFB1 (10mM) and NNK (200mM). This result correlated with the lack of CYP2A13 protein in the R101Q-CHO cells, although the genomic integration of transfected R101Q cDNA and the expression of R101Q messenger RNA were clearly demonstrated in these stable transfectants. Consistent with the possibility that the variation might reduce the protein stability, R101Q variant protein expressed in insect cells showed a loss of P450 peak and coumarin 7-hydroxylase activity as well as an increased susceptibility to limited protein digestion. Thus, the R101Q polymorphic change results in a null allelic variant of CYP2A13. Our results should be useful in designing and interpreting molecular epidemiological studies related to CYP2A13 genetic polymorphisms.
cytochrome P450 2A13, genetic polymorphism, metabolic activation, aflatoxin B1, 4-(, methylnitrosamino), -1-(, 3-pyridyl), -1-butanone.,
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王守林, Xiao-Yang He†, Lili Tang†, Shou-Lin Wang†, Qing-Song Cai, Jia-Sheng Wang and Jun-Yan Hong*
Int. J. Cancer: 118, 2665-2671(2006),-0001,():
-1年11月30日
The worldwide human exposure to aflatoxin B1 (AFB1), particularly in developing countries, remains to be a serious public health concern. Although AFB1 is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB1. Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB1 to exert its carcinogenicity. Previous studies have identified CYP1A2 and CYP3A4 as the major enzymes for AFB1 activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB1 in situ are unknown. In the present study, we demonstrate that CYP2A13, an enzyme predominantly expressed in human respiratory tract, has a significant activity in metabolizing AFB1 to its carcinogenic/toxic AFB1-8,9-epoxide and AFM1-8,9-epoxide at both low (15 lM) and high (150 lM) substrate concentrations. Under the same conditions, there was no detectable AFB1 epoxide formation by CYP2A6, which was also reported to be involved in the metabolic activation of AFB1. Consistent with the activity data, there was an ~800-fold difference in LC50 values of AFB1 (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 lM). We further demonstrate that amino acid residues Ala117 and His372 in CYP2A13 protein are important for AFB1 epoxidation and its related cytotoxicity. Our results suggest that CYP2A13-catalyzed metabolic activation in situ may play a critical role in human lung carcinogenesis related to inhalation exposure to AFB1.
cytochrome P450 2A13, aflatoxin B1, metabolic activation, cytotoxicity
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王守林, Shou-Lin Wang, Xiao-Yang He, and Jun-Yan Hong
DRUG METABOLISM AND DISPOSITION Vol. 33, No.3 33: 336-340, 2005,-0001,():
-1年11月30日
Cytochrome P450 (P450) enzymes play a critical role in the metabolic activation of a wide variety of environmental carcinogens. Recently, a novel human P450 enzyme, CYP2S1, has been identified. It is inducible by dioxin and other classical aryl hydrocarbon receptor ligands. However, little is known regarding the substrates and the functional role of CYP2S1. Since CYP2S1 is predominantly expressed in human lung and trachea, it is reasonable to speculate that CYP2S1 may play an important role in metabolizing the environmental chemicals to which human respiratory tissues are exposed. In the present study, we examined the activity of human CYP2S1 in the metabolism of nicotine and in the activation of three potent carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[a]pyrene (BaP), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The full-length CYP2S1 cDNA was amplified by nested polymerase chain reaction from a human lung cDNA library and was expressed in both Chinese hamster ovary (CHO) cells and Sf9 insect cells. In contrast to the positive controls, i.e., CHO cells expressing human CYP2A13 (for NNK activation) or human CYP1A1 (for BaP activation), there was no increase in NNK- or BaP-induced toxicity in the CHO cells expressing CYP2S1. The heterologously expressed CYP2S1 proteins showed no detectable activity in metabolizing nicotine and PhIP. These results clearly demonstrate that CYP2S1 does not catalyze the metabolism of nicotine and the metabolic activation of these lung carcinogens.
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【期刊论文】Effect of Genetic Variation on Human Cytochrome P450 Reductase-Mediated Paraquat Cytotoxicity
王守林, Jing-Fen Han, Shou-Lin Wang, Xiao-Yang He, Chun-Yong Liu, and Jun-Yan Hong
TOXICOLOGICAL SCIENCES 91(1), 42-48(2006),-0001,():
-1年11月30日
Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) is a widely used herbicide and is highly toxic to human and animals. The mechanisms of paraquat toxicity involve the generation of superoxide anion through the process of redox cycling. NADPHcytochrome P450 oxidoreductase (POR) has been reported to be a major enzyme for one-electron reduction of paraquat that initiates the redox cycling. Recently, a total of six missense variants of human POR have been identified in patients with discorded steroidogenesis. However, the effect of these genetic variations on POR-mediated paraquat toxicity is not known. Using the Flp-In Chinese hamster ovary (CHO) cells stably expressing either mouse or human POR and the cells with POR knockdown by siRNA, we confirmed that POR is responsible for paraquat-induced cytotoxicity. We further used this validated system to compare paraquat-induced toxicity among the cells that stably expressed wild-type human POR and its natural variants. While there was no difference in paraquat-induced toxicity between the cells expressing wild-type human POR and the Cys569Tyr variant, the toxicity in cells expressing all the other variants (Tyr181Asp, Ala287Pro, Arg457His, Val492Glu, and Val608Phe) was significantly decreased. Our results provide further evidence on the important role of POR in paraquatinduced toxicity and suggest that individuals carrying the functional variant POR alleles may have an altered susceptibility to paraquat exposure.
NADPH-cytochrome POR, paraquat, genetic variants, Flp-In CHO cells, siRNA knockdown.,
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