Activity of cytochrome P450 in children

The 6β-hydroxycortisol/cortisol ratio was measured in 52 children aging 1.1–14.0 years. The maximum increment in this ratio occurred in the age interval of 1.1–2.0 years. During this period, the regression coefficients in the linear (r=0.57;p=0.044) and nonlinear logarithmic models (r=0.56;p=0.049) were similar. At the age of 10–14 years, the examined ratio attained 19.17±17.79. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 9, pp. 272–274, September, 2004     

Activity of cytochrome P450 in children

The 6-hydroxycortisol/cortisol ratio was measured in 52 children aging 1.1–14.0 years. The maximum increment in this ratio occurred in the age interval of 1.1–2.0 years. During this period, the regression coefficients in the linear (r=0.57; p=0.044) and nonlinear logarithmic models (r=0.56; p=0.049) were similar. At the age of 10–14 years, the examined ratio attained 19.17±17.79.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 9, pp. 272–274, September, 2004     

中国肾移植患者中细胞色素P450 3A4的新突变位点

背景：环孢素A在人体内主要经过细胞色素P450 3A4代谢。已有研究表明细胞色素P450 3A4基因多态性影响环孢素A的药代动力学,而且环孢素A慢性肾毒性主要是由于环孢素A在体内的长期蓄积。因此推测细胞色素P450 3A4基因多态性可能是肾移植移植后环孢素A 慢性肾毒性的主要原因之一。 目的：分析细胞色素P450 3A4基因多态性与肾移植移植后环孢素A 慢性肾毒性的相关性。 方法：纳入200例服用环孢素A的肾移植患者参加此项研究,其中105例经肾活检和(或)血肌酐值的变化诊断为环孢素A 慢性肾毒性,其他95例未发生肾毒性)。采集受试者外周静脉血并提取基因组DNA,采用聚合酶链式反应和直接测序法检测细胞色素P450 3A4基因外显子5,7,9和12的点突变。 结果与结论：中国肾移植患者中发现3个细胞色素P450 3A4新突变位点,即336 A>G,837 G>A 和406 A>C。其中 3例肾移植患者可检测出336 A>G,8例肾移植患者可检测出837 G>A。新突变点406 A>C仅发现于3例环孢素A慢性肾毒性患者,在非肾毒性患者中未发现新突变位点,且406 A>C可导致细胞色素P450 3A4保守区136位苏氨酸(Thr)转变为苯丙氨酸(Phe)。文章未发现已报道的中国人群细胞色素P450 3A4基因在外显子5,7,9和12的多态性。结果证实,文章在中国肾移植患者中发现了3个细胞色素P450 3A4的新突变位点336 A>G,837 G>A 和406 A>C,其中406 A>C可能引起细胞色素P450 3A4酶活性的改变。     

New specific marker of cytochrome P450 1A2 activity

Various methods were proposed for phenotyping of patients by activity of cytochrome P450 1A2, each has some advantages and disadvantages. However, no reference parameters were developed for measuring CYP1A2 activity that could be used as a unified standard for phenotyping of patients. We propose a mathematic model of caffeine metabolism allowing calculation of rate constants for the formation of its primary metabolites. First-order rate constant of paraxanthine formation was tested as a new specific marker of isoenzyme 1A2 in healthy volunteers.     

细胞色素P450 2A6的多态性研究

细胞色素P450 2A6(cytochrome P450 2A6，CYP2A6)是主要的尼古丁C-氧化酶和香豆素7-羟化酶。对已发现的CYP2A6的等位基因及其对CYP2A6活性的影响，CYP2A6的多态性和个体吸烟行为及肺癌、食管癌的易感性的关联进行综述。     

广州地区汉族人群细胞色素P450 1A1和细胞色素P450 2E1基因多态性

目的 探讨广州地区汉族人群细胞色素Ｐ４５０ １Ａ１（ＣＹＰ１Ａ１）和细胞色素Ｐ４５０ ２Ｅ１（ＣＹＰ２Ｅ１）基因的多态性分布规律。方法 用ＰＣＲ－ＲＦＬＰ和等位基因特异性扩增技术,对１５０名广州地区汉族正常人的ＣＹＰ１Ａ１和ＣＹＰ２Ｅ１基因多态性进行了检测,并与其他人群进行了比较。结果 ＣＹＰ１Ａ１基因３’端非翻译区的Ｍｓｐ１多态位点ｍ１（ＭＳＰⅠ－）、ｍ２（ＭｓｐⅠ＋）等位基因频率分别为６２．３     

Transcriptional activation of cytochrome P450 1A1 with α-tocopherol

Peroral administration of α-tocopherol in a daily dose of 150 mg/kg for 1, 4, 8, and 12 days leads to induction of cytochromes P450 1A in male rats. Activity of CYP1A1 and CYP1A2 increased most significantly one day after α-tocopherol administration (by 2.6 and 2.7 times, respectively). CYP1A1 was immunohistochemically detected in rat liver microsomes during this period. The content ofCYP1A1 mRNA significantly increased in the liver. The amount ofCYP1A2 mRNA and regulatory proteins for signal activation of CYP1A1 (AhR andArnt) remained unchanged after treatment with α-tocopherol. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 9, pp. 264–267, September, 2004     

新型细胞色素P450氧化酶的发现与筛选

细胞色素P450是一类被广泛研究的依赖于血红素的氧化酶,因它在还原状态下能与CO结合形成复合物,在450nm附近有最大吸收峰而命名为细胞色素P450。P450首先在哺乳动物肝微粒体中被发现。迄今为止,已经命名的P450有12000多个。     

A neutrophil-derived cytochrome P450-dependent metabolite of arachidonic acid modulates neutrophil behavior

Recently, the metabolism of arachidonic acid to two unidentified products (Peak 1 and Peak 2) by a cytochrome P-450 dependent mixed function oxidase has been described in canine polymorphonuclear leukocytes (PMNs). This study assessed the biologic activity of one of these metabolites, Peak 2, on PMN function. Peak 2 was formed biologically following addition of exogenous arachidonic acid to canine PMNs pretreated with BW755c to inhibit lipoxygenase and cyclooxygenase enzymes, and purified by high performance liquid chromatography following separation by column chromatography. Peak 2 (20-200 ng/ml) inhibited calcium ionophore A23187-induced aggregation and the second phase of LTB4-induced aggregation. Additionally, Peak 2 inhibited A23187-induced PMN adhesion to columns of Sephadex G-25. BW755c (94 microM), which increased the formation of Peaks 1 and 2 by almost 300%, also inhibited A23187-induced PMN adhesion. In contrast, Peak 2 did not inhibit the release of superoxide anions or immunoreactive LTB4, after stimulation of the PMNs with A23187. Thus, Peak 2 may modulate some activities of canine PMNs. Because the biologic activity of Peak 2 is opposite to that of LTB4, which promotes PMN aggregation and adhesion, and because LTB4 may be metabolized by a cytochrome P-450-dependent mixed function oxidase to less active metabolites, this enzyme system may play a central role in the control of PMN function.     

Purification of a soluble cytochrome P450 from Trichosporon montevideense

The yeast Trichosporon montevideense CBS 6721 expressed large amounts of cytochrome P450 after cultivation in a glucose-peptone medium. The P450, which could be detected in the cytosolic fraction after cell breakage and ultracentrifugation, was purified to electrophoretic homogeneity and migrated in SDS-PAGE with a M(r) of 43,000. As indicated by IEF, the preparation consisted of two different P450 isoforms with pI-values of 5.9 and 6.2, which were named P450MS1 and P450MS2 respectively. Both isoforms had a characteristic maximum at 446 nm in the reduced carbon monoxide difference spectra. Partial N-terminal sequencing of P450MS1 and P450MS2 demonstrated a high degree of sequence homology between the soluble P450 enzymes of T. montevideense CBS 6721 and their close relationship to the soluble P450 forms of Trichosporon spec. SBUG 752, T. cutaneum ATCC 58094 and to the P450s of the CYP55 family of Fusarium oxysporum and Cylindrocarpon tonkinense.     

Profiling the expression of cytochrome P450 in breast cancer

Murray G I, Patimalla S, Stewart K N, Miller I D & Heys S D
(2010) Histopathology 57 , 202–211 Profiling the expression of cytochrome P450 in breast cancer Aims: The cytochrome P450s (P450) are key oxidative enzymes that metabolize many carcinogens and anticancer drugs. Thus, these enzymes influence tumour development, tumour response to therapy and are putative tumour biomarkers. The aim was to define the P450 expression profile in breast cancer and establish the significance of P450 expression in this tumour type. Methods and results: A tissue microarray containing 170 breast cancers of no special type was immunostained for a panel of 21 P450s. The highest percentage of strong immunopositivity in breast cancers was seen for CYP4X1 (50.8%), CYP2S1 (37.5%) and CYP2U1 (32.2%), while CYP2J (98.6%) and CYP3A43 (70.7%) were the P450s that most frequently displayed no immunoreactivity. CYP4V2 (P = 0.01), CYP4X1 (P = 0.01) and CYP4Z1 (P = 0.01) showed correlations with tumour grade. CYP1B1 (P = 0.001), CYP3A5 (P = 0.001) and CYP51 (P = 0.005) showed the most significant correlations with oestrogen receptor status. Correlations with survival were identified for CYP2S1 (P = 0.03), CYP3A4 (P = 0.025), CYP4V2 (P = 0.026) and CYP26A1 (P = 0.03), although none of these P450s was an independent marker of prognosis. Conclusions: This study has defined the expression profile of cytochrome P450s in breast cancer and may offer their potential application as biomarkers to aid decisions regarding optimal adjuvant hormonal therapy.     

肝富集的转录因子与细胞色素P450基因的表达调控

细胞色素P450(cytochromeP450,CYP)是含血红素酶家族,广泛存在于从细菌到哺乳动物中,参与氧化或还原代谢多种内源和外源化合物。如内源性甾体激素、维生素和脂肪酸衍生物的合成与分解,外源性药物、杀虫剂、环境污染物和致癌物的代谢[1]。CYP1-4家族主要代谢外源化合物,它们表现     

Genetically modified macrophages expressing hypoxia regulated cytochrome P450 and P450 reductase for the treatment of cancer

This study describes a combined gene and cell therapy based on the genetic modification of primary human macrophages, as a treatment for cancer. Here, we have utilised the tumour-infiltrating properties of macrophages as vehicles to deliver a gene encoding a prodrug-activating enzyme such as human cytochrome P450 2B6 (CYP2B6) inside tumours followed by killing the tumour cells with the prodrug cyclophosphamide (CPA). Macrophages were transduced with an adenoviral vector that expresses human cytochrome CYP2B6 via a synthetic hypoxia responsive promoter (OBHRE) and with human P450 reductase (P450R), via the CMV promoter. In the presence of CPA, these genetically modified macrophages showed increased cytotoxicity against various tumour cell lines compared to untransduced macrophages or macrophages transduced with CYP2B6 alone. In human ovarian carcinoma xenograft models, the median survival of mice treated with genetically modified macrophages plus CPA increased up to two-fold compared to the survival of mice treated with untransduced macrophages and CPA. Genetically modified autologous macrophages may be a feasible therapeutic option for the treatment of some solid tumours, such as ovarian cancer.     

Molecular interactions between human cytochrome P450 1A2 and flavone derivatives

Activation by human cytochrome P450 1A2 (hCYP1A2) of heterocyclic amines is assumed to trigger of a number of carcinogenic processes. In this work, a group of natural inhibitors of human cytochrome P450 1A2 reported in literature has been theoretically analysed. These consist of flavone hydroxylated derivatives, natural compounds that exist in plants and associated products. Different theoretical/computational tools were used to describe the specific molecular interactions between these compounds and hCYP1A2. Based on this analysis, a method is proposed for helping the selection of specific molecular features that enhance protein-inhibitor interaction.