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.     

A review of the hepatotoxicity of paracetamol at therapeutic or near-therapeutic dose levels, with particular reference to alcohol abusers

The number of published reports associating hepatotoxicity with paracetamol ingestion at therapeutic or near-therapeutic dose levels is small but is, nevertheless, suggestive of a relationship. There is however, mounting evidence that certain groups of patients, such as alcohol-dependent people, patients receiving enzyme-inducing drugs (particularly anti-convulsant and anti-tuberculosis medications) as well as those with certain infectious diseases, are rendered more susceptible to paracetamol-induced hepatotoxicity. Seventy-four case reports where therapeutic or near-therapeutic doses of paracetamol resulted in hepatic injury are reviewed and factors and mechanisms which might explain this apparently increased vulnerability to damage are discussed.     

The physiological and pharmacological roles of cytochrome P450 isoenzymes

The cytochrome P450 isoenzymes are a superfamily of haemoprotein enzymes that catalyse the metabolism of a large number of endogenous and exogenous compounds. Recently, the cytochrome isoenzymes have been shown to be important in the synthesis of steroid hormones and bile acids, the arachidonic acid cascade and in central nervous function. These enzymes are a major determinant of the pharmacokinetic behaviour of numerous drugs. Furthermore, alterations in cytochrome P450 activity have been implicated in some diseases.     

Diazepam metabolism in human foetal and adult liver

Summary Diazepam was metabolized by human foetal liver microsomes to N-desmethyldiazepam and N-methyloxazepam as early as the 13th week of gestation. The metabolic activity was lower than that of microsomes from adult human liver. Diazepam was shown mainly to be hydroxylated to N-methyloxazepam at substrate concentrations higher than 0.1 mM. Diazepam levels above 1.0 mM were inhibitory to the overall metabolic reaction. SKF 525-A inhibited diazepam metabolism by foetal liver microsomes at a concentration of 0.1 mM. The addition of diazepam to foetal and adult human liver microsomes resulted in a type II spectral change. Its inhibition by carbon monoxide indicated that biotransformation of diazepam was performed by the cytochrome P-450-linked mono-oxygenase system.     

氯氮平在体内代谢与细胞色素P450 1A2-2964位点多态性的关系

目的：探讨氯氮平在精神分裂症患者体内代谢和细胞色素P450 1A2－2964位点多态性关系，指导临床对不同患者合理使用氯氮平。方法：采用固定剂量给药，用高效液相色谱法（HPLC）测定血药浓度，用限制性片段长度多态性（RFLPs）分析基因型。结果：吸烟组和非吸烟组之间比较，吸烟组血浆氯氮平浓度低，去甲氯氮平／氯氮平比值高（P＜0．05，P＜0．01），P450 1A2-2964位点等位基因G的频率为0．75，A的频率为0．25，在非吸烟患者中，去甲氯氮平／氯氮平在w/w基因型与非w/w基因型(w/m m/m)之间无显著的统计学意义（P＞0．05），在吸烟患者中，w/w基因型去甲氯氮平／氯氮平要高于非w/w基因型（P＜0．05），在吸烟患者和非吸烟患者中w/w基因型之间比较，吸烟患者的去氯氮平／氯氮平明显高于非吸烟患者（P＜0．01）；而非w/w基因型之间无显著的统计学意义（P＞0．05），结论：吸烟能诱导P450 1A2的活性。P450 12-2964位点等位基因均为G（w/w)时诱导能力最强，发生G→A突变时，诱导能力降低，分析患者P450 1A2 G－2964A的多态性，对合理使用氯氮平有意义。     

Review Article Cytochromes P450 in fungi

Summary. The article gives an overview on the history of the discovery of P450 cytochromes and on their occurrence in nature, especially on their interactions with metabolic pathways in fungi. The significance of the P450 cytochromes in the ergosterol synthesis as well as in the inhibitory mechanisms caused by imidazole and triazole antimycotics is described is detail. Zusammenfassung. Der Artikel gibt eine Übersicht über die Entdeckungsgeschichte der P450-Cytochrome und ihr Vorkommen in der Natur. Insbesondere wird eingegangen auf das Vorkommen der P450-Cytochrome in Pilzen und ihre Interaktionen mit Stoffwechselprozessen der Pilzzellen. Die Bedeutung der P450-Cytochrome für die Ergosterol-Synthese der Pilze und für deren Hemmechanismen durch Imidazol- und Triazol-Antimykotika wird im Detail dargestellt.     

芳香化酶P450在子宫内膜异位症中的表达及意义

目的：探讨芳香化酶P450在子宫内膜异位症发病中的作用。其阳性表达用于诊断子宫内膜异位症可行性。方法：应用免疫组化方法检测正常子宫内膜和子宫内膜异位症的在位及异位内膜芳香化酶P450的表达。结果：芳香化酶P450在正常子宫内膜无表达或弱阳性，在子宫内膜异位症的在位和异位内膜均有强表达，且增殖期高于分泌期表达，敏感度为92％，特异度为95．5％。结论：子宫内膜芳香化酶分泌增加促进子宫内膜异位症的发生，并对其诊断有重要意义。     

中国广东籍汉族人细胞色素P450_2E_1基因5'侧翼区多态性

目的：探讨中国广东籍汉族人细胞色素Ｐ４５０２Ｅ１基因５′侧翼区的多态性分布规律。方法：利用聚合酶链反应和ＲｓａⅠ、ＰｓｔⅠ限制性片段长度多态性（ＰＣＲＲＦＬＰ）技术对８２名正常中国广东籍汉族人的细胞色素Ｐ４５０２Ｅ１基因５′侧翼区的多态性进行了检测。结果：８２名正常中国广东籍汉族人的细胞色素Ｐ４５０２Ｅ１基因５′侧翼区Ｃ１（ＲｓａⅠ＋,ＰｓｔⅠ）、Ｃ２（ＲｓａⅠ,ＰｓｔⅠ＋）等位基因频率分别为０８５４,０１４６;基因型Ｃ１Ｃ１、Ｃ１Ｃ２、Ｃ２Ｃ２的比率分别为０７３２、０２４４、００２４,符合ＨａｒｄｙＷｅｉｎｂｅｒｇ平衡分布。结论：中国广东籍汉族人细胞色素Ｐ４５０２Ｅ１基因５′侧翼区ＲｓａⅠ和ＰｓｔⅠ多态性分布规律与欧美人显著不同。