细胞色素P450酶系在人鼻咽癌及鼻咽非癌组织中的表达

背景与目的：鼻咽癌(nasopharyngeal carcinoma,NPC)的发生与环境及遗传因素密切相关。环境中各种前致癌物需经代谢酶包括细胞色素P450(Cytochrome P450,CYP450)的活化才具有致癌作用。本研究拟检测鼻咽癌及鼻咽非癌组织中的CYP450基因表达,以了解与鼻咽部组织中致癌物代谢活化有关的CYP450基因。方法：利用下述两种方法检测CYP450基因的表达：(1)混合7例鼻咽非癌组织的RNA构建cDNA文库,进行克隆测序及生物信息学分析;(2)逆转录14例鼻咽癌组织及8例鼻咽非癌组织的RNA为cDNA,以PCR扩增检测CYP450基因的表达。结果：cDNA文库检测的CYP450基因EST(Expressed SequenceTag)有CYP1Bl、CYP2F1、CYP2J2、CYP4B1、CYP4F12、CYP5A(TBXAS1)、CYP20A1和CYP51A1,其中CYP481的EST拷贝数最高,达16个拷叭;RT—PCR检测表达的CYP450基因有CYP1A1、CYP1B1、CYP2A6、CYP2A13、CYP286、CYP2C8、CYP2C9、CYP2D6、CYP2El、CYP2Fl、CYP3A4、CYP3A5、CYP3A7、CYP4B1,其中CYP1B1、CYP286、CYP481已经在文库检测有表达。总共有19个CYP450基因在鼻咽癌及鼻咽非癌组织表达,表达较高的基因有CYP1B1、CYP2C8、CYP2C9、CYP2D6、CYP3A5和CYP481。结论：鼻咽部组织表达CYP450基因种类较多,其中包括与前致癌物代谢活化相关的基因。     

CYP1A1和CYP1B1基因多态性与中国妇女Ⅰ型子宫内膜癌的相关性

目的 探讨细胞色素P450 1A1（CYP1A1）和细胞色素P450 1B1（CYP1B1）基因多态性与Ⅰ型子宫内膜癌遗传易感性与流行病学高危因素的关系。方法 采用SNPshot技术,检测103例Ⅰ型子宫内膜癌患者和100例对照人群CYP1B1、CYP1A1和NQO1基因共8个位点的多态性分布,分析其与Ⅰ型子宫内膜癌易感性及肥胖、高血压等流行病学高危因素的相关性。结果 CYP1A1基因SNP位点rs4646421基因型在两组间分布频率差异有统计学意义（P<0.05）,与携带CT基因型者相比,携带CC基因型的个体罹患子宫内膜癌的风险较小（OR=0.479, 95%CI: 0.255~0.899）,携带T等位基因的个体子宫内膜癌的发病风险高于C等位基因携带者（OR=1.796, 95%CI: 1.203~2.680）。与携带CC基因型相比,携带TC+TT基因型在年龄>60岁、BMI≥25、绝经延迟（超过52岁）、并发高血压的女性中Ⅰ型子宫内膜癌的发病风险增加。CYP1B1基因SNPrs1056836在两组间的分布频率差异无统计学意义（P>0.05）,但发生更多的碱基胞嘧啶变异为鸟嘌呤,可能会使罹患Ⅰ型子宫内膜癌的风险增加（OR=0.604, 95%CI: 0.369~0.990）。结论 CYP1A1基因SNP位点rs4646421多态性增加了Ⅰ型子宫内膜癌的发病风险,并且与流行病学高危因素有关,有望成为Ⅰ型子宫内膜癌筛查的潜在指标。     

细胞色素P450 1A2的转基因细胞及其应用

1引言 细胞色素P450(CYP是一种含血红素酶,广泛分布于从细菌到动物中,能代谢各种外源性和内源性化合物.动物肝微粒体中的CYP能代谢外源性物质,如药物、农药、环境污染物、前突变物和/或前致癌物.细胞色素P450 1A2(CYP1A2)能代谢芳香胺、杂环胺、黄曲霉素B1等许多类化合物.转CYP1A2的各种细胞系的建立为研究CYP1A2的功能提供了新的工具.到目前为止,已经建立的细胞系有细菌、酵母菌、昆虫细胞和哺乳动物细胞.最近,CYP1A2和其他微粒体电子转运系统如NADPH-细胞色素P450还原酶共同表达成功,提高了异源性CYP1A2的代谢能力.另外,为了重建杂环胺的完全代谢活化系统,建立了同时表达CYP1A2和二相酶(phase Ⅱ enzyme)N-乙酰转移酶的细胞系.各种永生的细胞系已经在毒理学试验领域内取得发展.下面按不同的细胞系说明它们的应用.     

CYP2E1基因多态性与肺癌易感性关系的研究进展

肺癌是最常见的恶性肿瘤,其发生发展与吸烟、大气污染、危险因素暴露及基因变异等多种因素有关,由细胞色素P450(CYP450)基因家族所编码的细胞色素P450酶系(Cytochrome P450s)所组成的Ⅰ相酶介导氧化代谢,具有重要的解毒功能.CYP2E1是CYP450基因家族重要成员之一,大量研究表明其基因多态性与肺癌易感性密切相关,但研究结果不一致.     

CYP1A1、CYP2E1基因多态性与癌症易感性的研究进展

人类细胞色素P450（CYP450）在多种内源性及外源性物质的生物代谢中起重要作用。大多数CYP450存在基因多态性,其中CYP1A1、CYP2E1两个基因多态性与癌症的发生密切相关。本文综述了近年来人类细胞色素P4501A1（CYP1A1）和P4502E1（CYP2E1）与癌症易感性之间关系的研究进展。     

155例汉族男性人群5-羟色胺受体1B基因单核苷酸多态性的特征分析

目的： 探讨中国汉族男性人群中5-羟色胺受体1B基因(HTR1B)单核苷酸多态性(SNP)的遗传特征。方法：通过基因再测序筛查155例汉族男性人群HTR1B基因多态性位点,采用HaploView软件分析筛查到的多态性位点的遗传学特征、连锁不平衡(LD)、标签SNP和单体型(域)分布。结果：155例汉族男性人群中,HTR1B基因SNP位点包含5′-侧翼区的rs17273700(-860A>G)、rs1228814(-700G>T)、rs11568817(-262 A>C)、rs130058(-161T>A),编码区的rs6298(+129A>G)、rs6296(+861G>C)和3′-侧翼区的rs6297(+1 180T>C);各多态性位点基因型频率均符合Hardy-Weinberg平衡(P>0.05);rs17273700与rs11568817位点之间(|D′|=1.0, r2=0.94)和rs6296与rs6298位点之间(|D′|=0.946,r2=0.849)呈强LD关联;该人群主要存在8种单体型,占94.2%,其中最主要为野生单体型H1(46.0%);筛选出-860A>G、-700G>T、-161T>A、+129A>G、+1 180T>C共5个标签SNP和两个单体型域,-860A>G和+129A>G分别为其代表性单体型标签SNP(htSNP)。结论：本研究首次筛查出HTR1B基因在中国汉族男性人群中的合适的标签SNP和htSNP,减少了后续研究的SNP位点数目,为探讨其与疾病的关系奠定了基础。     

CYP2E1基因多态性与客家人群胃癌易感性的研究

目的：通过研究细胞色素P4502E1（CYP2E1）基因多态性位点rs2031920与客家人群胃癌遗传易感性的相关性,探讨遗传和环境因素在胃癌发病中的作用。方法采取病例-对照研究,选择经胃镜和病理检查确诊的梅州地区客家人群51例胃癌患者（胃癌组）和52例正常对照（对照组）,对CYP2E1 rs2031920（C-1053T）位点进行基因型及等位基因检测,分析其在两组间的分布特征。结果CYP2E1 rs2031920位点在梅州地区客家人群中存在 CC、CT、TT 多态性,各基因型在胃癌组的分布频率为62．75％（32／51）、33．33％（17／51）、3．92％（2／51）,在对照组的分布频率为59．62％（31／52）、34．61％（18／52）、5．77％（3／52）,两组之间的差异无统计学意义（χ2＝0．235,P ＝0．889）。CYP2E1基因rs2031920位点的等位基因 C、T 在胃癌组和对照组构成比分别为79．41％（81／102）、20．59％（21／102）和76．92％（80／104）、23．08％（24／104）,差异无统计学意义（χ2＝0．186,P ＝0．666）。经性别、年龄分层分析结果显示也无统计学意义（χ2＝4．412,P ＝0．129;χ2＝0．898,P ＝0．473）。结论 CYP2E1的基因多态性位点 rs2031920与客家人群胃癌的易感性不相关。     

CYP2D6基因多态性在乳腺癌中的价值

细胞色素P450(cytochrome P450,CYP450)酶系属于单加氧酶,是一种以血红素为辅基的b族细胞色素超家族基因代谢酶,因其还原态的吸收峰在450 nm处而命名。CYP450具有解毒作用,通常可将脂溶性有毒物质代谢为水溶性物质,使有毒物质排出体外。CYP2D6是CYP450家族中的一员,是一种重要的参与外源性物质在体内代谢的酶。研究[1]表明,CYP2D6     

PTEN基因单核苷酸多态性与喉癌的关联分析

目的:探讨中国汉族人群PTEN基因与喉癌的关联性。方法:通过生物信息学方法在公共SNP数据库中查找该基因2个SNP位点,用PCR-RFLP法对汉族人群散发喉癌患者(91例)和对照组(104例)进行分型、病例-对照关联分析及单倍型分析。结果:基因型频率分析表明,2个SNP均符合Hardy-Weinberg平衡,P均>0.05。病例对照分析显示,rs2735343与喉癌相关,χ2=6.447,P=0.014;rs701848与喉癌不相关,χ2=0.12,P=0.720。单倍体型分析表明,rs2735343-rs701848单倍体型与喉癌密切相关,χ2=12.92,P=0.0048。结论:PTEN本身或其邻近位点与中国汉族人群喉癌发生密切相关。     

Ⅰ、Ⅱ相药物代谢酶遗传多态性与晚期非小细胞肺癌化疗疗效的关系

背景与目的目前药物代谢酶遗传多态性与化疗疗效关系的研究结果多不一致,本研究旨在探讨细胞色素P4501A1(cytochrome P450 1A1,CYP1A1)、2E1(cytochrome P450 2E1,CYP2E1)、2D6(cytochrome P450 2D6,CYP2D6)和谷胱甘肽硫转移酶M1(glutathione S-transferase M1,GSTM1)基因多态性与晚期非小细胞肺癌化疗疗效以及与肺癌患者预后的关系。方法采用PCR和PCR-RFLP技术对肺癌患者4种药物代谢酶基因分型,并对他们进行5年跟踪随访。结果携带B型CYP1A1和缺陷性GSTM1肺癌患者比其它基因型患者化疗疗效好(P<0.001)。携带A型CYP1A1肺癌患者接受非铂类化疗药物治疗比B型和C型患者疗效好(P=0.041);携带缺陷性GSTM1肺癌患者接受铂类化疗药物治疗疗效比功能型患者疗效好(P=0.011)。4种酶对晚期非小细胞肺癌患者总生存期(overall survival,OS)没有明显影响(P>0.05)。结论 A型CYP1A1肺癌患者接受非铂类化疗药物治疗比B型和C型患者疗效好;缺陷性GSTM1肺癌患...     

Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans

The aim of the present study was to evaluate the effects on the susceptibility to colorectal cancer (CRC) of genetic polymorphisms in P-glycoprotein (PGP) and the metabolic enzymes cytochrome P450 1A2 (CYP1A2) and flavin-containing monooxygenase 3 (FMO3). We analyzed five single-nucleotide polymorphisms (SNP) in 93 cancer-free volunteers and 111 patients with CRC: one common genetic variant of the PGP-encoding MDR1 gene and four SNP in genes for metabolic enzymes (two SNP in FMO3 and two SNP in CYP1A2). The genotypes and allele frequencies of the MDR1/C3435T, FMO3/G488A, FMO3/A923G and CYP1A2/G-3860 A polymorphisms were not significantly different in cancer-free subjects and CRC patients. However, a significant association was found between the CYP1A2/A-163C polymorphism and the risk of CRC, particularly in elderly (>55 years) subjects and smokers. A phenotyping study in normal smokers showed that the CYP1A2 activity of subjects with the CYP1A2/-163 AA genotype was significantly lower than that of subjects carrying the CYP1A2/-163C allele. Combined results show that the CYP1A2/-163C allele is significantly associated with an increase in CYP1A2 activity and a consequent increased risk of CRC in Koreans, particularly in elderly people and smokers.     

Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers.

PURPOSE: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1 were also independent markers of prognosis. CONCLUSIONS: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1 in primary ovarian cancer were independent markers of prognosis.     

Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis.

PURPOSE: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91 lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009). CONCLUSIONS: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51 or CYP2S1 were associated with poor prognosis and CYP51 is an independent marker of prognosis.     

Co-expression of human CYP1A1 and a human analog of cytochrome P450-EF in response to 2,3,7,8-tetrachloro-dibenzo-pdioxin in the human mammary carcinoma-derived MCF-7 cells

Cultured human mammary carcinoma (MCF-7) cells exhibited constitutivecytochrome P450-dependent metabolism of 7,12-dimethylbenz[a]anthracene(DMBA) (45–75 pmol/mg microsomal protein). Exposure ofthe cells to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), whichis known to induce CYP1A1, not only resulted in a 30-fold increasein the total microsomal metabolism of DMBA but produced substantialdifferences in the distribution of DMBA metabolites formed.This suggested that different cytochrome P450 (P450) forms predominatedin untreated and induced cells. Comparative studies with TCDD-inducedhuman hepatoblastoma (HepG2) and skin cell carcinoma (SCC-13)cells and also recombinantly expressed human CYP1A1, confirmedthat the DMBA metabolite profile in TCDD-induced MCF-7 cellswas that of human CYP1A1. This distribution, however, differedsubstantially from the regioselectivity of rat CYP1A1 and mouseCypla-1. Rabbit antibodies to rat CYP1A1 completely inhibitedthe DMBA-metabolizing activity of TCDD-induced MCF-7 cells buthad no inhibitory effect on constitutive DMBA metabolism whichwas, however, completely inhibited by chicken antibodies tothe novel P450 in mouse embryo fibroblasts (P450-EF). Anti-P450-EFinhibited only 10% of the DMBA-metabolizing activity in theTCDD-induced MCF-7 cell microsomes. Microsomes from untreatedMCF-7 cells expressed a 52 kDa protein that was immunodetectableby rabbit anti-P450-EF and failed to express immunodetectablelevels of human CYP1A1. DMBA metabolism, therefore, s from P450-EFin uninduced microsomes to CYP1A1 in TCDD-induced microsomes.The mobility of the P450-EF-like protein in MCF-7 cells washigher than that of P450-EF from C3H/10T1/2CL8 (10T1/2) cells(55 kDa). The 52 kDa protein from MCF-7 cells was induced     

细胞色素P450花生四烯酸表氧化酶对肿瘤细胞增殖的影响

背景与目的：细胞色素P450（cytochromeP450，CYP）花生四烯酸表氧化酶对内皮细胞具有促进增殖、抑制凋亡的作用。本研究主要探讨CYP表氧化酶对肿瘤细胞增殖的影响，并初步探讨其影响细胞增殖的相关信号转导机制。方法：用重组腺相关病毒（recombinant adeno-associatedvirus，rAAV）介导CYP花生四烯酸表氧化酶基因CYP2J2（cytochromeP4502J2）、CYPF87V（cytochromeP450F87V）和反义CYP2J2基因分别转染A549、Tea-8113、HepG2、Ncl-H4464种肿瘤细胞．采用MTT法、细胞计数法和流式细胞术分析CYP表氧化酶对肿瘤细胞增殖的影响：并用Westernblot法检测转染前后Tca-8113细胞中表皮生长因子受体（epidermal growth factor receptor，EGFR）、ERKI／2和Akt磷酸化水平：最后将转染rAAV-CYP2J2、rAAV-CYPF87V、rAAV-antiCYP2J2和rAAV-GFP的Tca-8113细胞分别接种至裸鼠皮下，观察皮下移植瘤的牛长情况。结果：转染CYP2J2和CYPF87V后，A549、Tca-8113、HepG2和Ncl-H446细胞的细胞增殖数分别是相应未转染细胞的1．7倍和2．0倍、1．4倍和1．5倍、1．6倍和1．8倍、2．2倍和2．0倍；转染反义CYP2J2阻断细胞自身CYP2J2表达后，上述4种细胞增殖显著减低：流式细胞术结果显示转染CYP表氧化酶基fj；I的肿瘤细胞中S／G2／M期细胞增加了210％。Westernblot结果显示，转染CYP2J2基因后，EGFR、ERK1／2和Akt磷酸化水平分别为未转染细胞的2倍、2．3倍和2．4倍，同时P13K表达水平也L调为未转染细胞的1．9倍：相反．转入反义CYP2J2基因明显抑制这些蛋白的磷酸化和表达。在体皮下移植瘤实验结果显示，转染rAAV-CYP2J2、rAAV—CYPF87V组裸鼠皮下移植瘤出现的时间（分别为5．8d和6．0d）明显较对照组和转染rAAV—GFP组（分别为8．4d和8．6d）短：而转染反义rAAV-CYP2J2组移植瘤生长缓慢，出现时间也明显较长（约10d）。结论：CYP花生四烯酸表氧化酶能促进肿瘤细胞     

SAM肝细胞色素P4503A对衰老的作用

大鼠肝细胞色素Ｐ４５０含量与年龄相关的变化是由特异的细胞色素Ｐ４５０酶引起的。探讨衰老与细胞色素Ｐ４５０３Ａ的活性是否有关。本文用红霉素Ｎ－脱甲基酶活性测定法分别检测了ＳＡＭ－Ｒ１、ＳＡＭ－Ｐ１和ＳＡＭ－Ｐ８三组衰老加速鼠中肝微粒体细胞色素Ｐ４５０３Ａ的活性。每动动物分为７ｗｋ、３６ｗｋ组。结果发现ＳＡＭ－Ｐ１和ＳＡＭ－Ｐ组中随年龄增长,ＣＹＰ３Ａ的活性均降低。１３ｗｋ时,ＳＡＭ－Ｐ１组ＣＹＰ３活     

CYP2D6 and CYP2E1 Gene Polymorphisms and their Association with Cervical Cancer Susceptibility: A Hospital Based Case-Control Study from South-Western Maharashtra

Background: In last few years several studies all over the world discovered the genetic polymorphisms in different cytochrome P450 genes associated with risk of various cancers, but contradictory outcomes were evidenced in case of cervical cancer risk.  In this case-control study we aimed to see whether the polymorphism of CYP2D6 or CYP2E1 genes may or may not be associated with cervical cancer risk in women of rural Maharashtra. Methods: In this case-control study, the association of CYP2D6 and CYP2E1 gene polymorphism with cervical cancer risk was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted with 350 clinically confirmed cervical cancer patients and 350 healthy women in a population of South-Western Maharashtra. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated, where p ≤0.005 was considered as statistically significant. Results: After the analysis of SNP (rs389209) of CYP2D6 and SNPs (rs2031920, rs6413432, rs6413420) of CYP2E1, we noticed that variant allele A of CYP2E1*6 showed significant increase in cervical cancer cases (OR=4.81; 95% CI: 1.57- 14.77; p=0.005). The genotypic distribution of heterozygote G/A genotype of CYP2D6*4 showed negative association with cervical cancer development when age of cancer occurrence (OR=0.41; 95% CI: 0.27- 0.61; p<0.0001) and tobacco history (OR=0.35; 95% CI: 0.20- 0.59; p=0.0001) was considered. Conclusion: The findings from this study supported that rs6413432 SNP of CYP2E1*6 increased cervical cancer risk in the studied rural women population.     

Cytochrome P450 isoenzyme mRNA expression pattern in human urinary bladder malignancies and normal urothelium

This study was designed to analyze the cytochrome P450 isoenzyme mRNA expression pattern of transitional cell carcinomas of the bladder (N = 19) and normal urothelium (N = 10). In addition, biopsies from normal urothelium (N = 32) taken at the time of transurethral resection of bladder cancer in eight patients from surrounding histologically normal urothelium also were characterized concerning their specific cytochrome P450 mRNA expression pattern. A total of 13 of 19 of the analyzed tumor specimens (68%) revealed expression of cytochrome P450 1B1. Cytochrome P450 4B1 and 1A1 mRNA expression were detected in 79% (15 of 19) and 53% (10 of 19) of the tumor specimens, with no correlation between tumor stage and grade of the neoplasm. Biopsies from macroscopically and histologically normal urothelium from tumor-invaded bladders also showed expression of cytochrome P450 1B1 in 75% (24 of 32), 4B1 in 62.5% (20 of 32), and 1A1 in 50% (16 of 32). Furthermore, a 75% homology concerning cytochrome P450 1B1 and 4B1 mRNA expression was observed between the bladder tumor and the biopsies from this bladder. The polymerase chain reaction analysis of normal urothelium from normal bladders that do not harbor a neoplasm revealed CYP450 mRNA expression for CYP450 1A1 in 6 of 10; 1B1 in 5 of 10; 4B1 in 6 of 10; 2D6 in 2 of 10; and 2E1 in 2 of 10. According to our data, CYP450 1B1 mRNA expression is not tumor-specific. The present findings are the first to compare CYP450 expression in bladder cancer with biopsies from the same tumor-bearing bladder, and they indicate that, from the enzymatic point of view, bladder cancer also is a panurothelial field disease present in even normal urothelium.