21－羟化酶CYP21B基因Ile~（172）→Asn错义突变

为了解先天性肾上腺皮质增生症患者的２１－羟化酶ＣＹＰ２１Ｂ基因中Ｉｌｅ~（１７２）→Ａｓｎ错义突变的发生率，根据放大受阻突变体系（Ａｍｐｌｉｆｉｃａｔｉｏｎｒｅｆｒａｃｔｏｒｙｍｕｔａｔｉｏｎｓｙｓｔｅｍ，ＡＲＭＳ）的要求，设计了３种引物：５＇ｄ（ＴＴＧＧＧＡＧＡＣＴＡＣＴＣＣＣＴＧＣＴＣＴ）３＇（共同引物）、５＇ｄ（ＡＧＧＴＧＡＧＧＴＡＡＣＡＧＡ）３＇（正常引物）、５＇ｄ（ＡＧＧＴＧＡＧＧＴＡＡＣＡＧＴ）３＇（突变引物），在７例患儿中进行了检测，发现具有本突变者３例。对其中一例进行的家系分析，结果提示：这组引物有快速、简便的优点，不需使用同位素就能对具有Ｉｌｅ~（１７２）→Ａｓｎ变异的高危家庭成员作产前诊断。     

Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3′-flanking region

Genetic differences in the metabolism of carcinogens may codetermine individual predisposition to cancer. Cytochrome P-4501A1 (CYP1A1) metabolically activates precarcinogens in cigarette smoke, such as benzo(a)pyrene, which is also an inducer of CYP1A1. Two point mutations have been reported, m1 in the 3-flanking region (6235T to C), and m2 within exon 7 (4889A to G), the latter leading to an isoleucine to valine exchange. In the Japanese population ml and m2 are correlated with lung cancer, suggesting an increased susceptibility to cigarette smoking related lung cancer. We studied 142 lung cancer and 171 reference patients in an ethnically homogeneous German group for m1 and m2 mutations by restriction fragment length polymorphism and allele-specific polymerase chain reaction, respectively. No statistically significant difference was found in the distribution of m1 alleles between lung cancer and controls; the frequency was 8.5% and 7.3% of the alleles, respectively (odds ratio = 1.17). A trend to an overrepresentation of ml alleles was observed among 52 squamous cell carcinoma patients (odds ratio = 1.65). In contrast, the frequency of m2 alleles in lung cancer patients was twofold higher (6.7%) than in the reference group (3.2%; odds ratio = 2.16; 95% confidence limits 0.96–5.11, P = 0.033); the odds ratio of m2 alleles in squamous cell carcinoma was 2.51 (95% confidence limits 0.85–7.05, P = 0.05). There was a close genetic linkage of m2 to m1 (10 of 11 reference patients), but a significantly higher number of cancer patients showed no linkage compared to the controls (odds ratio = 8.89, 95% confidence limits 0.83–433, P = 0.04). Thus no association was found between presence of ml alleles and lung cancer, but, in contrast, m2 alleles proved as a hereditary risk factor, especially if not linked with m1 alleles.Abbreviations Ah aryl hydrocarbon - CYP1A1 cytochrome P4501A1 - CYP1A1 CYP1A1 gene - PCR polymerase chain reaction - PY pack years - RFLP restriction fragment length polymorphism Correspondence to: N. Drakoulis     

Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1

Injection of microparticle-encapsulated DNA elicits immune responses to plasmid-encoded antigens in mice and humans. Cytochrome P450 CYP1B1 (CYP1B1) is a member of the CYP1 P450 enzyme family that is overexpressed in a variety of solid tumors. The work described herein was performed to study the kinetics of stimulating T cell responsiveness with an encapsulated DNA encoding CYP1B1 and provides support for the clinical development of this formulation. Immunization of HLA-A2/Kb transgenic mice with human CYP1B1 encoding plasmid DNA formulated in poly(lactide-co-glycolide) (PLG) microparticles elicits CD8+ T cells that respond to human CYP1B1-positive target cells. The duration of the immune response, the effect on the immune response of multiple injections, and the safety of repeated injections were studied. These results show that the PLG-encapsulated DNA therapeutic elicits durable immune responses to CYP1B1, the responses are dependent on repeat immunization, and that the formulation is well tolerated.     

CYP1A1基因多态性与急性淋巴细胞白血病的关系

目的　探讨CYP1A1基因多态性与急性淋巴细胞白血病 (ALL)遗传易感性的关系。方法　应用PCR -RFLP、ASA技术 ,分析 78例ALL患者和 112例健康人CYP1A1基因多态性 ,比较ALL患者与对照组间频率差异。结果　ALL组CYP1A1MspI基因多态位点 ,各等位基因和基因型频率与对照组比较有显著性差异 (P <0 .0 5 ) ,其中等位基因m2使患ALL的危险度提高了 1.5 4倍 ,m1m2、m2m2基因型使患ALL的危险度分别提高了 2 .2 7倍和 2 .77倍 ;ALL组CYP1A1Ile-Val各等位基因和基因型频率与对照组比较无显著性差异 (P >0 .0 5 )。结论　CYP1A1MspI基因多态可能与ALL的发生有关。     

Cholecalciferol (Vitamin D<Subscript>3</Subscript>) Inhibits Growth and Invasion by Up-regulating Nuclear Receptors and 25-Hydroxylase (CYP27A1) in Human Prostate Cancer Cells

Epidemiological evidence suggests an inverse relationship between prostate cancer and serum vitamin D levels. We examined the ability of cholecalciferol (vitamin D₃), a calcitriol precursor, to inhibit or reverse cellular changes associated with malignant transformation and invasion and explored its mechanisms of action. The RWPE2-W99 human prostate epithelial cell line, which forms slow-growing tumors in nude mice, was used because it mimics the behavior of the majority of primary human prostate cancers. Cholecalciferol, at physiological levels: (i) inhibited anchorage-dependent and -independent growth; (ii) induced differentiation by decreasing vimentin expression with a concomitant decrease in motility/chemotaxis; (iii) decreased MMP-9 and MMP-2 activity with concomitant decrease in invasion; and (iv) exerted its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptor-α (RXR-α), and androgen receptor (AR) in a dose-dependent manner. Furthermore, we found that RWPE2-W99 prostate cancer cells, similar to RWPE-1 cells (Tokar and Webber. Clin Exp Metast 2005; 22: 265–73), constitutively express the enzyme 25-hydroxylase CYP27A1 which is markedly up-regulated by cholecalciferol. Cholecalciferol has effects similar to those of calcitriol on growth, MMP activity, and VDR. The ability of CYP27A1 to catalyze the conversion of cholecalciferol to 25(OH)D₃ and of 25(OH)D₃ to calcitriol has been reported. RWPE2-W99 cells, similar to RWPE-1 cells, appear to have the rare ability to locally convert cholecalciferol to the active hormone calcitriol. Because it can inhibit cellular changes associated with malignant transformation and invasion, we propose that cholecalciferol may be an effective agent for the treatment of prostate cancer.     

Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.     

Behavioral and neurochemical effects induced by subchronic combined exposure to toluene at 40 ppm and noise at 80 dB-A in rats

We investigated whether exposure to noise, in addition to its well-known potentiating effect on toluene-induced ototoxicity, may also exacerbate behavioral disturbances and brain neurochemical alterations produced by subchronic exposure to low toluene concentration. To test this hypothesis, we evaluated whether subchronic combined exposure (16 weeks, 104 h per week) to noise at 80 dB-A and toluene at 40 ppm potentiates the recently reported neurotoxic effects of subchronic exposure to 40 ppm toluene. Locomotor and rearing activities, sensitization to narcosis induced by acute toluene at high concentration, and tyrosine and tryptophan hydroxylase activities in the caudate-putamen and hippocampus were investigated in both male and female rats. Our results confirm that subchronic exposure to 40 ppm toluene significantly decreases rearing activity and leads to a sensitization to toluene-induced narcosis, as evaluated by loss of righting reflex, but fails to demonstrate any adverse effect of noise, alone or in combination with toluene. Given that toluene has addictive properties, the lack of potentiating behavioral and neurochemical effect of noise is discussed with regards to a recent study that has shown that methamphetamine neurotoxicity is potentiated by exposure to loud noise.     

PON1Q192R基因多态性与冠心病患者使用氯吡格雷疗效的关系

目的：探讨不同民族PON1Q192R等位基因变异频率以及PON1Q192R基因多态性与冠心病患者氯吡格雷抵抗（CR）的关联性。方法：纳入新疆医科大学第二附属医院2020年1月至2020年12月使用氯吡格雷且诊断为冠心病的患者127例,患者每日服用氯吡格雷75 mg,5 d后用血栓弹力图测定相关参数,并进行CYP2C19*2、CYP2C19*3、CYP2C19*17和PON1Q192R基因分型检测。结果：不同民族之间PON1Q192R基因突变频率差异具有统计学意义（P <0.05）,患者的血栓弹力图参数结果显示,PON1Q192R基突变并不会显著降低氯吡格雷疗效。结论：PON1Q192R基因突变频率与冠心病患者氯吡格雷反应的相关性还需要进一步研究。     

Differences in Caffeine 3-Demethylation Activity among Inbred Mouse Strains: A Comparison of Hepatic Cyp 1a2 Gene Expression between Two Inbred Strains

The 3-demethylation of caffeine can be used as an index of cytochromeP450 CYP1A2 activity in vivo. We compared the plasma levelsof caffeine and the 3-demethylated metabolite, 1,7-dimethylxanthine,in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J,and SWR/J) and one inbred strain (APN) derived in our laboratoryfrom outbred Swiss-Webster mice on the basis of its relativesusceptibility to acetaminophen-induced hepatotoxicity. We foundsignificant variations between a number of the common strains,all of which produced significantly higher caffeine 3-demethylationindices than our APN strain. In three of the six common strains,there was a significant difference between males and females,with the females having consistently lower 1,7-xanthine/caffeineratios. Hepatic Cyp1a2 expression was compared between APN andC3H/HeJ males. Microsomal methoxyresorufin O-demethylation,acetanilide 4-hydroxylation, and CYP1A2 immunoreactive proteinlevels were significantly higher in C3H/HeJ relative to APNmice, as were hepatic CYP1A2 mRNA levels. These results indicatethe importance of strain and gender to the outcome of pharmacologicalor toxicological studies involving CYP1A2-mediated metabolism,as well as the suitability of the plasma 1,7-dimethylxanthine/caffeineratio as a marker of CYP1A2 activity in the mouse. The strikingdifferences observed between the APN and C3H/HeJ mice suggestthat these strains may be suitable for a genetic analysis ofthe regulation of the basal expression of CYP1A2, a key enzymeIn procarcinogen activation.     

Effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers,major metabolites of phenytoin,on the occurrence of chronic-gingival hyperplasia: in vivo and in vitro study

The purpose of this study was to assess the possible role of the (R)- and (S)- enantiomers of the phenytoin metabolite p-HPPH in the pathogenesis of gingival hyperplasia (GH). About 98% of circulating p-HPPH is in the (S)-form. There were significant differences between patients with and without GH in (R)-p-HPPH level (0.055 vs 0.042 g·ml^–1), both enantiomer/racemate level ratios, and R/S enantiomeric ratio (0.0313 vs 0.0232); an increase in serum (R)-p-HPPH level was observed in patients with GH. In separate experiments, the effect of p-HPPH enantiomers on the proliferation of the normal human dermal fibroblast was studied. The in vitro study showed that (R)-p-HPPH selectively stimulated fibroblast growth. The results suggest that the least abundant metabolite, (R)-p-HPPH, is the most toxic with respect to gingival hyperplasia.