Induction of CYP1A by benzo[k]fluoranthene in human hepatocytes: CYP1A1 or CYP1A2?

While fresh human hepatocyte cultures are widely used to model hepatic cytochrome P450 (CYP) regulation and activity, their CYP1A subfamily composition induced by, e.g., polycyclic aromatic hydrocarbons is ambiguous. CYP1A1, CYP1A2, or both have been reported to be expressed, and their varied roles in chemical carcinogenesis makes resolution of which CYPs are expressed essential. We have used an immunoblot system with Bis-Tris-HCl-buffered polyacrylamide gel, which clearly resolves human CYP1A1 and CYP1A2, and polyclonal goat anti-human CYP1A1/CYP1A2 and rabbit anti-human CYP1A2 antibodies to probe the expressed CYP1A1 and CYP1A2 composition of seven individual human hepatocyte cultures induced with 5 microM benzo[k]fluoranthene (BKF) for 24 h. In six of the cultures only CYP1A1 was detected, and in the seventh both CYPs were detected. In most vehicle-treated hepatocyte cultures, neither CYP1A1 nor CYP1A2 was detected. In three additional hepatocyte cultures treated individually with BKF and 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), the resultant induced CYP1A1/1A2 profiles were essentially not influenced by the nature of the inducing agents. To develop an activity-based assay to differentiate between CYP1A1 and CYP1A2 expression in human hepatocytes, our previously published R warfarin assay (Drug Metab. Disp. (1995) 23, 1339-1345) was applied to TCDD (10 nM)-treated hepatocyte culture. The low concentration of TCDD did not produce inhibition of the warfarin metabolism-such inhibition could confound the results. Based on the ratios of 6- to 8-hydroxywarfarin formed in two cultures, the ratios of CYP1A1/CYP1A2 expressed in these cultures were determined and they agreed with the ratios determined by immunoblot analysis. Thus each individual human hepatocyte culture must be characterized for induced CYP1A1 and CYP1A2 expression in studies of CYP1A activity. The warfarin assay provides a means of characterizing the cultures.     

Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1

We report the synthesis and evaluation of a series of cholesterol side-chain analogs as mechanistic probes of three important Mycobacterium tuberculosis cytochrome P450 enzymes that selectively oxidize the ω-position of the methyl-branched cholesterol side-chain. To probe the structural requirements for the thermodynamically disfavored ω-regiospecificity we compared the binding of these substrate analogs to each P450, determined the turnover rates, and characterized the enzymatic products. The results are discussed in the context of the structure-activity relationships of the enzymes and how their active sites enforce ω-oxidation.     

Characterization of CYP1A enzyme in Adélie penguin liver

As CYP1A enzymes are induced by certain contaminants, their induction pattern has been used as a biomarker for exposure of certain pollutants. Ethoxyresorufin O-deethylase (EROD) activities are widely used in environmental assessments of polychlorinated biphenyls in many wildlife species. The EROD activity, a typical probe for CYP1A enzyme was studied in liver microsomes prepared from Adélie penguins (Pygoscelis adeliae) (n=10). Penguin liver microsomes (0.5 mg/mL) were incubated with the substrate ethoxyresorufin and NADPH at 37 degrees C for 10 min, and the reaction was terminated by addition of methanol. The formation of the metabolite resorufin was assayed by an HPLC method. EROD activity was present in all liver samples studied. Penguin liver microsomal fraction exhibits typical Michaelis-Menten kinetics in the O-deethylation of ethoxyresorufin. The data were best described by a biphasic kinetic model, which could be interpreted in terms of two populations of CYP enzyme. Mean (+/-S.D.) K(m) values for high- and low-affinity components of EROD were 51+/-109 (range: 0.16 to 358) and 872+/-703 (range: 303 to 2450) nM, respectively. The corresponding mean V(max) values for the high- and low-affinity enzyme activities were 1.8+/-1.4 (range: 0.21 to 5.1) and 9.6+/-3.7 (range: 6.0 to 18.3) pmol/min/mg. The EROD activity in penguin liver microsomes was inhibited by CYP1A inhibitors (phenacetin, 7-ethoxycoumarin and proportional variant-naphthoflavone), whereas other CYP inhibitors for CYP2C9 (tolbutamide), 2C19 (mephenytoin), 2D6 (debrisoquin) and 2E1 (diethyldithiocarbamate) had no effect. These results suggest that CYP1A-like enzymes are present in penguin livers. The activity of this enzyme may be a useful biomarker for assessing the environmental impact of pollutants on Antarctic wildlife.     

A Systematically Combined Genotype and Functional Combination Analysis of CYP2E1, CYP2D6, CYP2C9, CYP2C19 in Different Geographic Areas of Mainland China – A Basis for Personalized Therapy

The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes—CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.     

紫杉醇对食蟹猴和人CYP1A2、CYP3A4及CYP2A6酶代谢的影响

目的探讨紫杉醇对食蟹猴和人肝微粒体CYP1A2、CYP2A6和CYP3A4酶活性的影响。方法采用食蟹猴和人肝脏微粒体,分别以非那西汀、睾丸酮和香豆素分别作为CYP1A2、CYP2A6、CYP3A4的底物,建立CYP1A2、CYP2A6和CYP3A4体外代谢体系。采用不同浓度的紫杉醇分别与上述3种底物共同孵育于肝微粒体代谢体系中。用HPLC法分别测定各底物的代谢产物扑热息痛、6β-羟基睾丸酮、7-羟基香豆素的产生量,计算IC50值,以评估紫杉醇对CYP1A2、CYP2A6和CYP3A4代谢的影响。结果紫杉醇对食蟹猴肝微粒体3种酶的IC50值分别为570±5.9μmol/L、140±2.9μmol/L和无影响;紫杉醇对人肝微粒体3种酶的IC50值分别为193±6.6μmol/L、253±3.6μmol/L和24±1.6μmol/L。结论紫杉醇对食蟹猴肝微粒体CYP1A2和CYP3A4活性具有一定的抑制作用,但对CYP2A6酶的活性几乎没有影响。紫杉醇对人肝微粒体CYP1A2和CYP3A4活性的抑制作用较弱,但对CYP2A6酶的活性抑制作用较强,提示临床上紫杉醇与作为上述酶底物的药物联合用药时应慎重,以避免因中西药物相互作用所导致的不良反应发生。     

Regioselective hydroxylation of 17β-estradiol by mutants of CYP102A1 from Bacillus megaterium

A large set of mutants of CYP102A1 from Bacillus megaterium have human cytochrome P450-like activities and the ability to metabolize a number of marketed drugs and steroids. Here, we tested whether the CYP102A1 mutants could be used to produce hydroxylated human metabolites of 17β-estradiol (E₂). A set of the mutants, which were generated by site-directed and random mutagenesis, was used to produce hydroxylated human metabolites of E₂ in this study. Some of the tested mutants could regioselectively generate 2-OH E₂ as a major metabolite but not other hydroxylated products. These results suggest that CYP102A1 mutants would be useful for the bioconversion of steroid hormones to hydroxylated products, which can be used for industrial applications.     

Enlarged analogues of uniconazole,new azole containing inhibitors of ABA 8′-hydroxylase CYP707A

We enlarged the uniconazole (UNI) molecule to find a specific inhibitor of abscisic acid (ABA) 8′-hydroxylase, and synthesized various UNI derivatives that were substituted with hydrophilic and hydrophobic groups at the 4-chlorine of the phenyl group of UNI using click chemistry. Considering its potency in ABA 8′-hydroxylase inhibition, its small effect on seedling growth, and its ease of application, UT4, the UNI derivative containing the C₄ alkyltriazole, was the best candidate for a highly selective inhibitor of ABA 8′-hydroxylase.     

Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions

Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC₅₀) was 1.1 ± 0.3 and 4.6 ± 0.3 μM for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with K_i of 1.6 and 2.0 μM, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4 ± 2.1 μM and 0.06 ± 0.01 min^–1 for K_I and k_inact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.     

A review of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17)

In the conventional P-450 dependent hydroxylation reaction, the Fe(III) resting state of the enzyme, by a single electron transfer, is reduced to Fe(II), which reacts with O(2) to produce a Fe(III)-O-O intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, Fe(III)-O-O(-), which after protonation leads to the fission of the O-O bond resulting in the formation of Fe(V)O, the key player in the hydroxylation process. Certain members of the P-450 family, including CYP17 and CYP19, catalyze, at the same active site, not only the hydroxylation process but also an acyl-carbon bond cleavage reaction which has been interpreted to involve the nucleophilic attack of the ferric-peroxyanion, Fe(III)-O-O(-), on the acyl carbon to furnish a tetrahedral intermediate which fragments, leading to acyl-carbon cleavage. Evidence is presented to show that in the case of CYP17 the attack of Fe(III)-O-O(-) on the target carbon is promoted by cytochrome b(5), which acts as a conformational regulator of CYP17. It is this regulation of CYP17 that provides a safety mechanism which ensures that during corticoid biosynthesis, which involves 17α-hydroxylation by CYP17, androgen formation is avoided. Finally, a brief account is presented of the inhibitors, of the two enzymes, which have been designed on the basis of their mechanism of action. Article from the Special issue on 'Targeted Inhibitors'.     

飞蝗CYP408B1和CYP409A1基因的原核表达

【目的】细胞色素P450是分布极其广泛的超家族酶,在昆虫内源及外源化合物代谢中发挥着重要的作用。本文分析了飞蝗Locusta migratoria CYP408B1和CYP409A1基因在不同组织部位的表达差异,并对两种蛋白进行原核表达,为其分子特性和生物学功能的深入研究提供基础资料。【方法】提取飞蝗5龄若虫不同组织部位的总RNA,体外反转录成c DNA,采用Real-time PCR和RT-PCR技术分析飞蝗CYP408B1和CYP409A1在不同组织部位的表达模式,构建表达载体p CW/CYP408B1、p CW/CYP409A1和p AC/CPR,将p CW/CYP408B1和p CW/CYP409A1分别与p AC/CPR在大肠杆菌Escherichia coli BL21(DE3)中进行共表达。【结果】通过PCR检测,发现CYP408B1和CYP409A1在飞蝗5龄若虫触角、脑、视叶、咽下神经节、胸神经节和附腺中均有表达,其中CYP408B1在附腺中表达量较高。原核表达结果显示,CYP409A1和CPR(NADPH细胞色素P450还原酶)均可表达,蛋白分子量分别约为58 ku和77 ku,但均为包涵体,而CYP408B1未能成功表达。【结论】本文揭示了飞蝗CYP408B1和CYP409A1在不同组织部位的表达模式,并对CYP409A1和CPR进行了原核表达,研究结果为深入探讨飞蝗细胞色素P450基因对杀虫剂的代谢解毒作用提供了实验依据和基础资料。     

飞蝗CYP408B1和CYP409A1基因的原核表达

【目的】细胞色素P450是分布极其广泛的超家族酶,在昆虫内源及外源化合物代谢中发挥着重要的作用。本文分析了飞蝗Locusta migratoria CYP408B1和CYP409A1基因在不同组织部位的表达差异,并对两种蛋白进行原核表达,为其分子特性和生物学功能的深入研究提供基础资料。【方法】提取飞蝗5龄若虫不同组织部位的总RNA,体外反转录成c DNA,采用Real-time PCR和RT-PCR技术分析飞蝗CYP408B1和CYP409A1在不同组织部位的表达模式,构建表达载体p CW/CYP408B1、p CW/CYP409A1和p AC/CPR,将p CW/CYP408B1和p CW/CYP409A1分别与p AC/CPR在大肠杆菌Escherichia coli BL21(DE3)中进行共表达。【结果】通过PCR检测,发现CYP408B1和CYP409A1在飞蝗5龄若虫触角、脑、视叶、咽下神经节、胸神经节和附腺中均有表达,其中CYP408B1在附腺中表达量较高。原核表达结果显示,CYP409A1和CPR(NADPH细胞色素P450还原酶)均可表达,蛋白分子量分别约为58 ku和77 ku,但均为包涵体,而CYP408B1未能成功表达。【结论】本文揭示了飞蝗CYP408B1和CYP409A1在不同组织部位的表达模式,并对CYP409A1和CPR进行了原核表达,研究结果为深入探讨飞蝗细胞色素P450基因对杀虫剂的代谢解毒作用提供了实验依据和基础资料。     

Lack of CYP1A responsiveness in species inhabiting chronically contaminated habitats: Two varieties of resistance?

Organisms chronically exposed to organic pollutants such as polychlorinated biphenyls (PCBs) can develop resistance to these chemicals, a condition associated with reduced inducibility of the biomarker enzyme cytochrome P450 1A (CYP1A). This study addresses the CYP1A response of members of the families Ictaluridae and Centrarchidae, two fish families found throughout much of the United States. We measured CYP1A expression, PCB body burdens, and conducted CYP1A challenge experiments in species from these families residing in the Town Branch/Mud River system (Logan County, KY, USA), a stream system historically contaminated with high levels of PCBs. Despite PCB concentrations in muscle tissue typically associated with elevated CYP1A (16.7 to 75.2μgPCB/g wet edible flesh), resident fish in the contaminated Town Branch/Mud River sites (yellow bullhead [Ameiurus natalis], green sunfish [Lepomis cyanellus], and spotted bass [Micropterus punctulatus]) had hepatic CYP1A activity levels similar to, rather than higher than, those in reference fish, suggesting reduced sensitivity to CYP1A induction. Lack of CYP1A expression following direct contaminant exposure has often been associated with resistance to those contaminants. To determine if CYP1A in resident populations was resistant to induction by PCBs, we exposed resident fish to a single, intraperitoneal injection with a potent CYP1A inducer, 3,4,3',4'-tetrachlorobiphenyl (PCB 77). PCB 77 treatment significantly induced hepatic CYP1A activity and protein in yellow bullhead from reference, but not contaminated, sites and had no effect on CYP1A in green sunfish from either site. The low CYP1A expression levels in resident fish with elevated PCB body burdens, together with the failure of PCB injection to induce CYP1A in certain populations, indicate an acclimatory CYP1A response in yellow bullheads and likely an inherently resistant CYP1A in green sunfish. This work demonstrates for the first time acclimation of CYP1A to PCBs in a species within the family Ictaluridae and provides further support for our previous work indicating an apparent inherent lack of CYP1A sensitivity to chlorinated inducers in Centrarchids. These traits may explain, at least in part, the common association of these families with degraded habitats and indicate Lepomis members are likely to be excellent candidates for exploring the mechanistic basis of 'inherent' CYP1A resistance. This study also underlines to the need for thorough characterization of the CYP1A responsivity of a population and/or species prior to using CYP1A as a reliable biomonitoring tool.     

CYP3A4基础与临床研究进展

细胞色素P4503A4(CYP3A4)是存在人类肝脏及肠道中的一种主要的细胞色素CYP450酶,约占成人肝脏CYP450酶总量的25%左右。临床中约有50%的药物是通过其代谢,并且其基因位点突变也与其多种疾病相关,知晓CYP3A4的表达水平和不同功能的遗传学基础,无论是对疾病的发病基础、临床药物的应用,会带来前所未有的启发,在药物应用过程中,通过对基因组学的认识,从而可以在基因层面了解个体代谢差异产生的原因,调整药物用量,提高疗效,最终使药物副作用降到最低限。目前对CYP3A4的研究渐趋于成熟,已逐渐阐明了其药物间相互作用的机制,它能够被多种药物竞争性抑制或者诱导,并受到某些蛋白受体的调控影响,可改变药物的药代动力学,增强或降低药效,造成个体用药差异,这也是造成药物间相互作用的重要原因。然而CYP3A4基因多态性与基因导向治疗关系,还有待进一步深入研究。该文对CYP3A4基因多态性、分布以及与临床疾病及用药的研究现状作一综述。     

Synthesis of ω-hydroxy dodecanoic acid based on an engineered CYP153A fusion construct

A bacterial P450 monooxygenase-based whole cell biocatalyst using Escherichia coli has been applied in the production of ω-hydroxy dodecanoic acid from dodecanoic acid (C12-FA) or the corresponding methyl ester. We have constructed and purified a chimeric protein where the fusion of the monooxygenase CYP153A from Marinobacter aquaeloei to the reductase domain of P450 BM3 from Bacillus megaterium ensures optimal protein expression and efficient electron coupling. The chimera was demonstrated to be functional and three times more efficient than other sets of redox components evaluated. The established fusion protein (CYP153A_{M. aq.}-CPR) was used for the hydroxylation of C12-FA in in vivo studies. These experiments yielded 1.2 g l^–1 ω-hydroxy dodecanoic from 10 g l^–1 C12-FA with high regioselectivity (> 95%) for the terminal position. As a second strategy, we utilized C12-FA methyl ester as substrate in a two-phase system (5:1 aqueous/organic phase) configuration to overcome low substrate solubility and product toxicity by continuous extraction. The biocatalytic system was further improved with the coexpression of an additional outer membrane transport system (AlkL) to increase the substrate transfer into the cell, resulting in the production of 4 g l^–1 ω-hydroxy dodecanoic acid. We further summarized the most important aspects of the whole-cell process and thereupon discuss the limits of the applied oxygenation reactions referring to hydrogen peroxide, acetate and P450 concentrations that impact the efficiency of the production host negatively.     

Semi-rational engineering of CYP153A35 to enhance ω-hydroxylation activity toward palmitic acid

Applied Microbiology and Biotechnology - CYP153A35 from Gordonia alkanivorans was recently characterized as fatty acid ω-hydroxylase. To enhance the catalytic activity of CYP153A35 toward...     

氯吡格雷对大鼠肝药物酶CYP3A4 和CYP1A2 表达的影响

目的：氯吡格雷主要由CYP3A4 催化使其激活,CYP1A2 也参与氯吡格雷活化。关于氯吡格雷对肝微粒体酶的影响国内外 文献报道不多,因此本实验通过检测肝细胞色素氧化酶CYP3A4 和CYP1A2 的表达,探讨氯吡格雷对大鼠肝药物酶的影 响。方法：生理盐水为对照组,氯吡格雷设高、中、低三个剂量组（27,13.5,6.75mg/kg/d）,雄性健康大鼠连续灌胃给药7天,脱臼处 死,取肝组织,通过western blot法检测大鼠肝脏CYP3A4 和CYP1A2 蛋白表达情况。结果：1）、氯吡格雷抑制大鼠CYP3A4 蛋白 表达,氯吡格雷高中低剂量组分别比生理盐水组大鼠CYP3A4 蛋白表达量降低（P<0.05）;氯吡格雷低中高剂量组间进行比较,大 鼠CYP3A4 蛋白表达量呈梯度减少（P<0.05）;2）、氯吡格雷抑制大鼠CYP1A2 蛋白表达,氯吡格雷高中低剂量组分别比生理盐水 组大鼠CYP1A2 蛋白表达量降低（P<0.05）,氯吡格雷低中高剂量组间进行比较,大鼠CYP1A2 蛋白表达量呈梯度减少（P<0.05）。 结论：氯吡格雷使肝细胞色素氧化酶CYP3A4 和CYP1A2 的表达量减少,因此氯吡格雷高、中、低3 个剂量组均不同程度的抑制 大鼠肝脏CYP3A4 和CYP1A2 的表达,提示当氯吡格雷与某些主要经CYP3A4 和CYP1A2 代谢的药物合用时,发生代谢性相关 作用的可能性大。     

氯吡格雷对大鼠肝药物酶CYP3A4和CYP1A2表达的影响

目的：氯吡格雷主要由CYP3A4催化使其激活,CYPlA2也参与氯吡格雷活化。关于氯吡格雷对肝微粒体酶的影响国内外文献报道不多,因此本实验通过检测肝细胞色素氧化酶CYP3A4和CYPlA2的表达,探讨氯吡格雷对大鼠肝药物酶的影响。方法：生理盐水为对照组,氯吡格雷设高、中、低三个剂量组（27,13．5,6．75mg／kg／d）,雄性健康大鼠连续灌胃给药7天,脱臼处死,取肝组织,通过westernblot法检测大鼠肝脏CYP3A4和CYPlA2蛋白表达情况。结果：1）、氯吡格雷抑制大鼠CYP3A4蛋白表达,氯吡格雷高中低剂量组分别比生理盐水组大鼠CYP3A4蛋白表达量降低（P〈0．05）;氯吡格雷低中高剂量组间进行比较,大鼠CYP3A4蛋白表达量呈梯度减少（P〈0．05）;2）、氯吡格雷抑制大鼠CYPlA2蛋白表达,氯吡格雷高中低剂量组分别比生理盐水组大鼠CYPlA2蛋白表达量降低（P〈0．05）,氯吡格雷低中高剂量组间进行比较,大鼠CYPlA2蛋白表达量呈梯度减少（P〈0．05）。结论：氯吡格雷使肝细胞色素氧化酶CYP3A4和CYPlA2的表达量减少,因此氯吡格雷高、中、低3个剂量组均不同程度的抑制大鼠肝脏CYP3A4和CYPlA2的表达,提示当氯吡格雷与某些主要经CYP3A4和CYPlA2代谢的药物合用时,发生代谢性相关作用的可能性大。     

“内异消”对子宫内膜异位症大鼠CYP1A2、CYP2E1、CYP3A4活性的影响

本文主要考察"内异消"对子宫内膜异位症大鼠肝微粒体CYP1A2、CYP2E1、CYP3A4活性的影响。将16只SD大鼠随机分为空白对照组、正常给药组,16只模型SD大鼠随机分为模型对照组和模型给药组。正常给药组和模型给药组每天灌胃给予"内异消",空白对照组和模型对照组灌胃给予羧甲基纤维素钠溶液,均连续给药7 d,于第8 d给予"Cocktail"探针药物咖啡因、氯唑沙宗和硝苯地平药物,通过HPLC检测Cocktail探针药物的代谢率评价各组CYP450及CYP1A2、CYP2E1、CYP3A4活性。结果表明,与正常组比较,模型对照组和模型给药组咖啡因、氯唑沙宗的t1/2减小,硝苯地平的t1/2延长,均无显著性差异(P0.05);与正常组比较,模型对照组和模型给药组咖啡因、氯唑沙宗的AUC(0-t)显著升高(P0.05),硝苯地平的AUC(0-t)的增加无显著性。说明"内异消"对子宫内膜异位症大鼠CYP1A2、CYP2E1、CYP3A4的活性不存在显著的相互作用。     

CYP3A基因表达与调控的分子机制

Ｐ４５０３Ａ是参与药的氧化代谢的重要酶系,在肝脏及肠道中含量丰富。人体内参与药物代谢的ＣＹＰ３Ａ亚系为ＣＹＰ３Ａ４、ＣＹＰ３Ａ５、ＣＹＰ３Ａ７。其中ＣＹＰ３Ａ７主要存在于胚胎肝脏。ＣＹＰ３Ａ的主要调控位于５端,其中某些转录调控因子结合位点与ＣＹＰ３Ａ在组织中的特异性表达有关。５端有两个特殊结构ＮＦＳＥ与ＨＦＬａＳＥ分别为ＣＹＰ３Ａ４与ＣＹＰＡ３Ａ７所独有,可能与基分别在成人及胚胎计中的特异性表达有