Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful

AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.

Studies on the Biomimetic Oxidation Catalyzed by the Model Compound of Cytochrome P-450 (Ⅶ) The Influence of the Axial Ligand X in TPPFe(Ⅲ)X on Its Catalytic Properties for the Oxygenation of Cyclohexane

In the study of cyclohexane monoxygenation with PhIO catalyzed by TPPFe( Ⅲ )X, we found the Influence of different axial ionic ligands X (X = F, Cl, Br, I, SCN, OR, R, CH,3, C2H6, (CH3)2CH, (CH2)3C)in TPPFe( Ⅲ )X on the oxidation products distribution and the yields of cyclohexanol. This paper deals with the linear relationship between the catalytic activity of TPPFe(Ⅲ)X and both the electronic or/ and steric effects of the axial ligands OR in TPPFe(Ⅲ)OR on its catalytic activity.

IMMUNOCHEMICAL IDENTIFICATION AND LOCALIZATION OF CYTOCHROME P-450HSjISOZYME, AN ENZYME RELATED TO NITROSAMINE METABOLISM, IN HUMAN GASTRIC MUCOSA AND GASTRIC CARCINOMA

Monoclonal antibody (MAb) to rat liver cyto-chrome P-450j isozyme, an activating enzyme specific to nitrosamine metabolism, was used coupled with immunoblotting, densitometer scanning of SDS-PAGE gels and immunohistochemical technique. The trace P-450HSj isozyme (Mr. 51.5 Kd) was found in human gastric mucosa. It was similar to P-450j in molecular weight, catalytic and immunochemical properties. The concentrations of P-450HSj in mucosa of lesser curvature were higher than those in greater curvature. This might be one of the important reasons that lesser curvature is the commonest area for gastric carcinoma. But there was possibly less P-450HSj in gastric mucosa with cancer. Im-munohistochemically, P-450HSj was discovered in the cytoplasm of some glandular epithelial cells, especially in the glands with hyperplastic and intestinal metaplastic changes adjacent to carcinoma. It was also found in some normal glands and in tumor cells of high-differentiated adenocarcinoma, but not in those of low-differentiated ones. Following subjects are discussed: (1) the method of detecting trace P-450HSj, (2) the rule of distribution of P-450HSj, and (3) the relationship between the isozyme and the occurrence of gastric cancer caused by nitrosa-mines.

Cytochrome P450 2E1 genetic polymorphism and gastric cancer in Changle,Fujian Province

AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2E1 polymorphisms are associated with risks of gastric cancer. METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including demographic characteristics, diet intake, and alcohol and tobacco consumption of individuals in our study were completed by a standardized questionnaire.PCR-RFLP revealed three genotypes:heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1. RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 individuals in gastric cancer group(6.6%), whereas there was only one in the control group (1.1%). However, there was no statistically significant difference between the two groups (two-tailed Fisher's exact test P=0.066). Individuals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR=1.50) and C2/C2 (OR=7.34) than individuals in control group (chi(2) =4.597, for trend P=0.032). The frequencies of genotypes with the C2 allele (C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele (C1/C1 genotype) among individuals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that individuals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer. CONCLUSION: Polymorphism of CYP2E1 gene may have some effect in the development of gastric cancer in Changle county, Fujian Province.

细胞色素P-448的生物学特性及其在化学物毒性中的作用

多年来的研究表明,细胞色素P-450依赖的混合功能氧化酶系有两个重要的作用。(1)生理作用:即参与体内的胆固醇、胆汁酸、类固醇、激素、维生素D等的生物合成与代谢。(2)解毒作用:许多外源性化学物(毒物、致癌物、药物等)都能经该酶系代谢成极性较大的产物,而易于从体内排出。细胞色素P-450是许多代谢酶的终末氧化酶。

Three new alternative splicing variants of human cytochrome P450 2D6 mRNA in human extratumoral liver tissue

AIM: To identify the new alternative splicing variants of human CYP2D6 in human extratumoral liver tissue with RT-PCR and sequencing. METHODS: Full length of human CYP2D6 cDNAs was amplificated by reverse transcription-polymerase chain reaction (RT-PCR) from a human extratumoral liver tissue and cloned into pGEM-T vector. The cDNA was sequenced. Exons from 1 to 4 of human CYP2D6 cDNAs were also amplificated by RT-PCR from extratumoral liver tissues of 17 human hepatocellular carcinomas. Some RT-PCR products were sequenced. Exons 1 to 4 of CYP2D6 gene were amplified by PCR from extratumoral liver tissue DNA. Two PCR products from extratumoral liver tissues expressing skipped mRNA were partially sequenced. RESULTS: One of the CYP2D6 cDNAs had 470 nucleotides from 79 to 548 (3' portion of exons 1 to 5' portion of exon 4), and was skipped. Exons 1 to 4 of CYP2D6 cDNA were assayed with RT-PCR in 17 extratumoral liver tissues. Both wild type and skipped mRNAs were expressed in 4 samples, only wild type mRNA was expressed in 5 samples, and only skipped mRNA was expressed in 8 samples. Two more variants were identified by sequencing the RT-PCR products of exons 1 to 4 of CYP2D6 cDNA. The second variant skipped 411 nucleotides from 175 to 585. This variant was identified in 4 different liver tissues by sequencing the RT-PCR products. We sequenced partially 2 of the PCR products amplified of CYP2D6 exon 1 to exon 4 from extratumoral liver tissue genomic DNA that only expressed skipped mRNA by RT-PCR. No point mutations around exon 1, intron 1, and exon 4, and no deletion in CYP2D6 gene were detected. The third variant was the skipped exon 3, and 153 bp was lost. CONCLUSION: Three new alternative splicing variants of CYP2D6 mRNA have been identified. They may not be caused by gene mutation and may lose CYP2D6 activity and act as a down-regulator of CYP2D6.

大鼠cyt p-448同工酶在致癌物活化中所起作用的一种评价方法

已知,多数化学致癌物经细胞色素(cyt)P-450、特别是经3-甲基胆蒽(MC)诱导的P-448同工酶代谢活化后,表现致癌和致突变活性。为了阐明在诱变试验中使用富含cyt P-448L或cyt

自来水有机浓集物对小鼠染色体的损伤及对肝脏细胞色素P448的诱导作用

本研究采用普通自来水，经ＸＡＤ－２树脂柱吸附获得自来水中有机浓集物。在相当于２００Ｌ／ｋｇ自来水的有机浓集物染毒条件下，小鼠骨髓ＰＣＥ微核率明显增高，而在小鼠睾丸染色体畸变分析中，５０Ｌ／ｋｇ剂量下即出现阳性结果。表明生殖细胞比体细胞对自来水中有机污染物更为敏感，在相同剂量下可能首先受到损害。本试验结果还表明，自来水中有机浓集物可诱导哺乳动物肝脏乙氧基异吩 唑Ｏ－脱乙基酶活性，即对细胞色素Ｐ４４８有诱导作用，表明本地区自来水中有机浓集物有一定的潜在致癌作用。

3种苯胺衍生物对大鼠肝脏S_9组分细胞色素P－448活性诱导的研究

用３种结构相似，但致癌／致突变强度不同的苯胺衍生物处理雄性Ｗｉｓｔａｒ大鼠，观察其对大鼠肝脏Ｓ９组分细胞色素Ｐ－４４８的诱导情况，结果见到有致癌作用的ＭＯＣＡ和ＭＤＡ可明显诱导大鼠肝脏Ｓ９组分细胞色素Ｐ－４４８活性，且强致癌剂ＭＯＣＡ的作用强于弱致癌剂ＭＤＡ；而无致癌作用的Ｄａｐｓｏｎｅ则未显现出诱导细胞色素Ｐ－４４８活性，这与它们的致癌／致突变能力相一致。本研究提示有可能用化学物诱导细胞色素Ｐ－４４８的能力来预测其致癌／致突变性。

Effect of cytochrome P-450 inhibitors on pharmacokinetics and safety of voriconazole

Our objective was to systematically assess the effect of cytochrome P-450（CYP450） inhibitors on pharmacokinetics and safety of voriconazole（VORI）. Cochrane Library, Pub Med, Embase, CNKI, CBM and Wan Fang databases and C linicaltrials.gov were searched up to Jan. 26～（th） 2016. Two reviewers independently identified studies, extracted data and assessed quality of studies. Meta-analysis was performed with Rev Man 5.3, and risk ratios（RRs） and mean differences（MDs） with 95% confidence intervals（CIs） were calculated. A total of 12 studies were included： three crossover randomized controlled trials, three single-arm before-and-after studies and six cohort studies. Compared with non-combination group, the group of VORI plus omeprazole had a significantly higher occurrence of hepatic dysfunction（RR = 4.11, 95% CI 1.12–15.08, P = 0.03）. However, neurologic dysfunction and visual disturbance were not significantly different. Pantoprazole, rabeprazole, cimetidine and contraceptive significantly increased the peak concentration（Cmax） and area under the curve（AUC） of VORI, while indinavir had no significant effect on pharmacokinetics of VORI. The effects of esomeprazole, erythromycin and azithromycin on pharmacokinetic parameters of VORI presented inconsistent results. Co-administration of VORI and CYP450 inhibitors was safe except for omeprazole. Although Cmax and AUC of VORI were increased while co-administered with a couple of CYP450 inhibitors, no significant effect on clinical outcomes was observed.

多氯联苯对大鼠脾脏EROD的诱导作用

本文报告用多氯联苯(PCB)200mg/kg对大鼠连续腹腔注射三日染毒,除可诱导肝脏微粒体乙氧基异吩噁唑脱乙基酶(EROD)活性增高外,在脾脏微粒体内也检出EROD活性(4.9pmol/min·mg蛋白质)。当PCB剂量为400mg/kg时,大鼠脾脏S_9组分中EROD活性为对照组的3.3倍。结果说明尽管脾脏本底的细胞色素P-448活性极低,但仍可被化学致癌物PCB诱导。

Induction of EROD activity in Paralichthys olivaceus by polychlorinated biphenyl CB-28

The test organisms (Paralichthys olivaceus) were exposed to CB - 28 with differentspiked concentrations. After 72 h, EROD activities in livers of the test organisms were measured. It was found that EROD activities significantly mounted up with the increase of spiked quantity. Therefore, there existed a dose-response relationship between EROD activities and specific pollutant concentrations. In the meantime, the optimal conditions for the analysis of EROD activity were discussed. The limitation of EROD activities as a monitoring parameter was also analyzed.

Metabolism of Praziquantel in Erythromycin, Acetylspi-ramycin and Dexamethasone Induced Rat Liver Micro-somes

Our results show that in liver microsomes from erythromycin,acetylspiramycin and dexamethsone pretreated rats,the rate of praziquantel( PQT)disappearence was increased as compared with control rat When microsomes from erythromycin-treated rats were exposed to PQT in the presence of potassium ferricyanide which broke down the cytochrome P-450 Fe(Ⅱ)-metabolite complexes and restored the functional cytochrome P-450,PQT metabolism was further increased. Acetylspiramycin did not form the complexes, so potassium ferricyanide showed no effect on the PQT metabolism in microsomes from acetylspiramycin-treated rats. Triacetyloleandomycin,a specific inhibitor of cytochrome P-450ⅢAI, inhibited PQT metabolism by 53% in liver microsomes from dexamethasone-treated rats.These results indicate the cytochrome P-450ⅢA seems to be involved in metabolism of PQT in rat liver microsomes.

Exposure to ambient air particulate matter and non-alcoholic fatty liver disease

The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM 2.5 impact the natural history of patients with obesity-related NAFLD,i.e. , development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.

Intravenous proton pump inhibitors for peptic ulcer bleeding:Clinical benefits and limits

Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality.Infusion with proton pump inhibitors(PPIs) prevents recurrent bleeding after successful endoscopic therapy.A gastric acidic environment of less than pH 5.4 alters coagulation function and activates pepsin to disaggregate platelet plugs.Gastric acid is secreted by H+,K+-ATPase,naming the proton pump.This update review focuses on the mechanism and the role of PPIs in the clinical management of patients with peptic ulcer bleeding.An intravenous omeprazole bolus followed by high-dose continuous infusion for 72 h after successful endoscopic therapy can prevent the recurrent bleeding.In the Asian,however,the infusion dosage can possibly be diminished whilst preserving favorable control of the intragastric pH and thereby still decreasing rates of recurrent bleeding.Irrespective of the infusion dosage of PPIs,rates of recurrent bleeding remain high in patients with co-morbidities.Because recurrent peptic ulcer bleeding may be prolonged in those with co-morbidities,a lowdose infusion of IV PPIs for up to 7-day may result in better control of recurrent bleeding of peptic ulcers.Due to the inter-patient variability in CYP2C19 genotypes,the infusion form of new generation PPIs,such as esomeprazole,should be promising for the prevention of recurrent bleeding.This article offers a comprehensive review of clinical practice,highlighting the indication,the optimal dosage,the duration,and the potential limitation of PPIs infusion for peptic ulcer bleeding.

CYP1A1,CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms

AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P < 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.

Effects of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on cytochrome P450 enzyme activities in rats

OBJECTIVE:To investigate the efficacy of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on cytochrome P450(CYP450)enzyme activities in rats.METHODS:A cocktail strategy was followed to evaluate the influence of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on the activities of CYP450 isoforms(CYP1A2,CYP3A4,CYP2E1,CYP2C19,CYP2C9,CYP2D6),which were determined by changes in the pharmacokinetic parameters of six probe drugs,theophylline,dapsone,chlorzoxazone,omeprazole,tolbutamide and dextromethorphan.Study groups included,Control group(CG),Tianma(Rhizoma Gastrodiae)group(TM),Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group(GT)and Tianma Gouteng(Gastrodia Uncaria)group(TMGT).RESULTS:No significant differences between Tianma(Rhizoma Gastrodiae)and control groups were found.Compared with the control group,in the Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group both the AUC and t1/2 of dapsone and tolbutamide were reduced,whereas the CL(clearance rate)of dapsone and tolbutamide were increased.Compared with the control group,in the Tianma Gouteng group,the AUC and t1/2 of dapsone and tolbutamide were reduced,the CL of dapsone and tolbutamide were increased,and the AUC and t1/2 of chlorzoxazone were increased and the CL of chlorzoxazone was reduced.CONCLUSION:Tianma(Rhizoma Gastrodiae)has no significant effect on the six CYP450 subtypes.The activities of CYP3A4 and CYP2C9 were increased by Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).The activities of CYP3A4 and CYP2C9 were increased,whereas the activity of CYP32E1 was reduced by combined Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).

GSTT1,GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population

AIM:To test the hypothesis that,in the Southeastern Brazilian population,the GSTT1,GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer. METHODS:We conducted a study on 100 cases of gastric cancer (GC),100 cases of chronic gastritis (CG),and 150 controls (C).Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR.CYP2E1/Pst1 genotyping was performed using a PCR-RFLP assay. RESULTS:No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups.However,a significant difference between CG and C was observed,due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group.The GSTT1 null genotype occurred more frequently in Negroid subjects,and the GSTM1 null genotype in Caucasians,while the GSTM1 positive genotype was observed mainly in individuals with chronic gastritis infected with H pylori. CONCLUSION:Our findings indicate that there is no obvious relationship between the GSTT1,GSTM1 and CYP2E1 polymorphisms and gastric cancer.

GSTM1,GSTT1,GSTP1 and CYP1A1 genetic polymorphisms and susceptibility to esophageal cancer in a French population:Different pattern of squamous cell carcinoma and adenocarcinoma

AIM:To evaluate the association between CYP1A1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma(SCC)and esophageal adenocarcinoma(ADC)in a high risk area of northwest of France. METHODS:A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles,GSTMI*2/*2 and GSTTl *2/*2 null genotypes).A total of 79 esophageal cancer cases and 130 controls were recruited. RESULTS:GSTMI*2/*2 and CYPIAI*IA/*2C genotype frequencies were higher among squamous cell carcinomas at a level dose to statistical significance(OR =1.83,95% CI 0.88-3.83,P=0.11;OR=3.03,95% CI 0.93-9.90,P=0.07, respectively).For GSTP1 polymorphism,no difference was found between controls and cases,whatever their histological status.Lower frequency of GSTT1 deletion was observed in ADC group compared to controls with a statistically significant difference(OR=13.31,95% CI 1.66-106.92,P<0.01). CONCLUSION:In SCC,our results are consistent with the strong association of this kind of tumour with tobacco exposure.In ADC,our results suggest 3 distinct hypotheses: (1)activation of exogenous procarcinogens,such as small halogenated compounds by GSTT1;(2)contribution of GSTT1 to the inflammatory response of esophageal mucosa,which is known to be a strong risk factor for ADC, possibly through leukotriene synthesis;(3)higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.

4.4′-亚甲基双(2-氯苯胺)对大鼠肝脏生物转化酶诱导能力的研究

用化学致癌剂4.4′-亚甲基双(2-氯苯胺)[MOCA]处理雄性大鼠后,可引起呈剂量依赖关系的乙氧基异吩恶唑酮O-脱乙基酶活性升高,同时伴有艾氏剂环氧化酶的活性下降MOCA还能引起几种其它生物转化酶的活性改变。本文结果表明,细胞色素P-448活性的诱导与化学物的致癌潜力有关。