Regulation of VDR expression in rat and human intestine and liver – Consequences for CYP3A expression

The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C α (PKCα) in rat and human ileum and liver using precision-cut slices. 1,25(OH)₂D₃ induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCα activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)₂D₃ and CDCA was inhibited by the PKCα inhibitor, bisindolyl maleimide I (Bis I). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)₂D₃ or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism.     

Effects of anthocyanins on the AhR–CYP1A1 signaling pathway in human hepatocytes and human cancer cell lines

Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food–drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)–cytochrome P450 CYP1A1 signaling pathway in human hepatocytes and human hepatic HepG2 and intestinal LS174T cancer cells. Pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) dose-dependently activated AhR, as revealed by gene reporter assay. PEL-2 and CYA-3 induced CYP1A1 mRNA but not protein in HepG2 and LS174T cells. Neither compounds induced CYP1A1 mRNA and protein in four different primary human hepatocytes cultures. The effects of PEL-2 and CYA-3 on AhR occurred by ligand-dependent and ligand-independent mechanisms, respectively, as demonstrated by ligand binding assay. In a direct enzyme inhibition assay, none of the antocyanins tested inhibited the CYP1A1 marker activity to less than 50% even at 100 μM concentration. PEL-2 and CYA-3 at 100 μM inhibited CYP1A1 to 79% and 65%, respectively. In conclusion, with exception of PEL-2 and CYA-3, there were no effects of 19 major anthocyanins and 3 food supplements containing anthocyanins on AhR–CYP1A1 signaling, implying zero potential of these compounds for food–drug interactions with respect to AhR–CYP1A1 pathway.     

Metabolism of (−)-fenchone by CYP2A6 and CYP2B6 in human liver microsomes

The in vitro metabolism of (?)-fenchone was examined in human liver microsomes and recombinant enzymes. The biotransformation of (?)-fenchone was investigated by gas chromatography-mass spectrometry. (?)-Fenchone was found to be oxidized to 6-exo-hydroxyfenchone, 6-endo-hydroxyfenchone and 10-hydroxyfenchone by human liver microsomal P450 enzymes. The formation of metabolites was determined by the relative abundance of mass fragments and retention times on gas chromatography (GC). CYP2A6 and CYP2B6 were major enzymes involved in the hydroxylation of (?)-fenchone by human liver microsomes, based on the following lines of evidence. First, of 11 recombinant human P450 enzymes tested, CYP2A6 and CYP2B6 catalysed the oxidation of (?)-fenchone. Second, oxidation of (?)-fenchone was inhibited by thioTEPA and (+)-menthofuran. Finally, there was a good correlation between CYP2A6, CYP2B6 contents and (?)-fenchone hydroxylation activities in liver microsomes of 11 human samples. CYP2A6 may be more important than CYP2B6 in human liver microsomes. Kinetic analysis showed that the V_max/K_m values for (?)-fenchone 6-endo-, 6-exo- and 10-hydroxylation catalysed by liver microsomes of human sample HG-03 were 24.3, 44.0 and 1.3?nM^?1?min^?1, respectively. Human recombinant CYP2A6 and CYP2B6 catalysed (?)-fenchone 6-exo-hydroxylation with V_max values of 2.7 and 12.9?nmol?min^?1?nmol^?1 P450 and apparent K_m values of 0.18 and 0.15?mM and (?)-fenchone 6-endo-hydroxylation with V_max values of 1.26 and 5.33?nmol?min^?1?nmol^?1 P450 with apparent K_m values of 0.29 and 0.26?mM. (?)-Fenchone 10-hydroxylation was catalysed by CYP2B6 with K_m and V_max values of 0.2?mM and 10.66?nmol?min^?1?nmol^?1 P450, respectively.     

Constitutive and induced expression by pyridine and β-naphthoflavone of rat CYP1A is sexually dimorphic

Adult male and female Sprague-Dawley rats were compared in terms of the constitutive levels and inducibility of CYP1A1 and CYP1A2 (CYP1A) in lung, kidney, and liver. CYP1A were induced by i.p. treatment with pyridine (75 mg/kg per day) or β-naphthoflavone (βNF; 25 mg/kg per day) for two consecutive days and analyzed catalytically (via O-dealkylation of resorufin ethers), at the protein level (by Western blot analysis) and at the mRNA level (by Northern blot analysis). In untreated rats, CYP1A1 protein and its mRNA were detectable only in the lung and kidney of females but not males, whereas CYP1A2 protein and its mRNA were detectable only in the liver in either gender. Pyridine treatment upregulated CYP1A1 mRNA and its protein in the lung, kidney and liver in female rats, and upregulated the mRNA but not the protein in the lung and liver in male rats. Conversely, pyridine induced both CYP1A2 mRNA and protein in the liver in female rats, whereas it induced the protein but not its mRNA in the liver in male rats. No gender difference was observed in the plasma elimination rate of administered pyridine. βNF, in contrast to pyridine, induced CYP1A proteins, activities, and mRNA to higher levels in male than in female rats. The results show that the constitutive as well as inducible expression of CYP1A is sexually dimorphic in the Sprague-Dawley rat, with females being more responsive than males to induction by pyridine but with males being more responsive than females to induction by βNF. The findings support the involvement of different mechanisms in CYP1A induction by pyridine and βNF. Received: 20 January 1999 / Accepted: 13 April 1999     

A review of phthalate pharmacokinetics in human and rat: what factors drive phthalate distribution and partitioning?

Abstract

Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of very high concern (SVHCs) in the EU, because of their toxicity for reproduction. However, high amounts of other phthalates are still produced and imported in the European Economic Area. In China and the US, recent studies show increasing concentrations of several phthalates in the air and in human urine, respectively. The understanding of phthalate absorption, distribution, metabolism, and elimination (‘pharmacokinetics’) in the organism is still limited. Specifically, phthalate partitioning among tissues is insufficiently understood. Here, we estimate partition coefficient (PC) values for different phthalates by using five algorithms and compare them to experimental (in-vivo and in-vitro) PC values. In addition, we review all pharmacokinetic steps for phthalates in human and rat, based on data from 133 peer-reviewed publications. We analyze the factors that determine phthalate partitioning and pharmacokinetics. Four processes are particularly relevant to phthalate distribution: protein binding, ionization, passive partitioning, and metabolism in different tissues. The interplay of these processes needs to be better represented in methods for determining the PC values of phthalates. The hydrophobicity of phthalates affects all pharmacokinetic steps. The exposure route has an influence on specific steps of phthalate pharmacokinetics but generally does not affect the pattern of metabolites in urine. The age of the organism has an influence on phthalate metabolism. More studies on the protein-bound fraction of phthalates in plasma and pharmacokinetic studies following inhalation and dermal exposure are desirable.     

Inhibition of human and rat 11β-hydroxysteroid dehydrogenases activities by bisphenol A

Bisphenol A (BPA) is a potential endocrine disruptor. It has been shown that it can interfere with steroid biosynthesis and metabolism. However, the mechanism is unclear. The objective of the present study is to investigate the effects of BPA on two isoforms of 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2) in human and rat tissues. Human liver, rat testis microsomes as well as rat adult Leydig cells were used for measurement of 11β-HSD1 activity, and human and rat kidney microsomes for 11β-HSD2 activity. BPA inhibited human and rat 11β-HSD1 activities with the half maximal inhibitory concentrations (IC₅₀s) of 14.81 ± 0.06 μM (mean ± SEM) for human and 19.39 ± 0.09 μM for rat enzyme, respectively. BPA inhibited rat 11β-HSD1 activity in intact rat Leydig cells. BPA also weakly inhibited both human and rat 11β-HSD2 activities. At 100 μM, BPA inhibited human and rat enzymes by 51.16% and 41.61%, respectively. In conclusion, BPA is an inhibitor for both 11β-HSD1 and 11β-HSD2, with selectivity against the type I enzyme.     

An expressional system of human cytochrome P-450 CYP1A1 gene transcription

目的：在人ＨｅｐＧ２细胞系上，建立人细胞色素Ｐ４５０ＣＹＰ１Ａ１（ＣＹＰ１Ａ１）基因转录的表达系统．方法：瞬时转染含人ＣＹＰ１Ａ１启动子的质粒（ｐＭＣ６３Ｋ）、ＥＬＩＳＡ法测定报道基因氯霉素乙酰转移酶（ＣＡＴ）的含量和酶学测定ＣＹＰ１Ａ１活性．结果：β萘黄酮２．５μｍｏｌ·Ｌ－１明显增强ＣＡＴ表达和ＣＹＰ１Ａ１活性（Ｐ＜０．０１）；在２．５－１０μｍｏｌ·Ｌ－１范围内，ＣＡＴ表达随浓度增高而不断增强，而ＣＹＰ１Ａ１活性则接近最高水平；１０μｍｏｌ·Ｌ－１时它们的作用强度分别为对照组的９４．３和２．８倍．用这种方法对八种含不同侧链的芥子油苷进行检测的结果表明，芸苔苷的水解产物（而非吲哚３原醇）诱导ＣＹＰ１Ａ１基因表达．结论：ＣＹＰ１Ａ１基因转录表达系统具有较高的可靠性和灵敏度     

Assessment of the impact of CYP3A polymorphisms on the formation of α-hydroxytamoxifen and N-desmethyltamoxifen in human liver microsomes

Tamoxifen, an antiestrogen used in the prevention and treatment of breast cancer, is extensively metabolized by cytochrome P450 enzymes. Its biotransformation to α-hydroxytamoxifen (α-OHT), which may be genotoxic, and to N-desmethyltamoxifen (N-DMT), which is partially hydroxylated to 4-hydroxy-N-DMT (endoxifen), a potent antiestrogen, is mediated by CYP3A enzymes. However, the potential contribution of CYP3A5 and the impact of its low-expression variants on the formation of these metabolites are not clear. Therefore, we assessed the contributions of CYP3A4 and CYP3A5 and examined the impact of CYP3A5 genotypes on the formation of α-OHT and N-DMT, by using recombinant CYP3A4 and CYP3A5 and human liver microsomes (HLM) genotyped for CYP3A5 variants. We observed that the catalytic efficiency [intrinsic clearance (CL(int))] for α-OHT formation with recombinant CYP3A4 was 5-fold higher than that with recombinant CYP3A5 (0.81 versus 0.16 nl · min?1 · pmol cytochrome P450?1). There was no significant difference in CL(int) values between the three CYP3A5-genotyped HLM (*1/*1, *1/*3, and *3/*3). For N-DMT formation, the CL(int) with recombinant CYP3A4 was only 1.7-fold higher, relative to that with recombinant CYP3A5. In addition, the CL(int) for N-DMT formation by HLM with CYP3A5*3/*3 alleles was approximately 3-fold lower than that for HLM expressing CYP3A5*1/*1. Regression analyses of tamoxifen metabolism with respect to testosterone 6β-hydroxylation facilitated assessment of CYP3A5 contributions to the formation of the two metabolites. The CYP3A5 contributions to α-OHT formation were negligible, whereas the contributions to N-DMT formation ranged from 51 to 61%. Our findings suggest that polymorphic CYP3A5 expression may affect the formation of N-DMT but not that of α-OHT.     

Relative roles of CYP2C19 and CYP3A4/5 in midazolam 1′-hydroxylation

1. During the characterization of recombinant CYP2C19, it was observed that this enzyme metabolized midazolam, which is generally regarded as CYP3A4/5 substrate, and we therefore decided to pursue this observation further.

2. CYP2C19 showed a Michaelis-Menten pattern for midazolam 1′-hydroxylation and was inhibited by (+)-N-3-benzylnirvanol and S-mephenytoin, which are a standard potent inhibitor and a substrate of CYP2C19, respectively.

3. The inhibitory potency by CYP3A4/5 inhibitor on the midazolam 1′-hydroxylation in human liver microsomes (HLM) was correlated with the CYP3A4/5 specific catalytic activity, but such correlation was not observed in CYP2C19 enzyme. The in vitro intrinsic clearance value for midazolam 1′-hydroxylation was not changed by the addition of (+)-N-3-benzylnirvanol in four individual HLM preparations.

4. These results indicated that although CYP2C19 is capable of catalyzing midazolam 1′-hydroxylation, CYP3A4/5 play a more important role.     

Bradykinin and B₂ receptor antagonism in rat and human articular chondrocytes

BACKGROUND AND PURPOSE

In osteoarthritis (OA), bradykinin (BK) is known to contribute to pain and synovitis, but not to cartilage degradation. Here, we investigated effects of BK and its antagonists on chondrocytes, cells involved in cartilage homeostasis.

EXPERIMENTAL APPROACH

BK receptor density and affinities of BK, its analogues and antagonists were measured in cultured human and rat chondrocytes by radioligand binding. Effects of BK were assessed by accumulation of inositol phosphates (IP) and release of interleukin (IL)-6 and IL-8.

KEY RESULTS

Density of [³H]-BK binding sites was higher (13–30-fold) and BK evoked a greater (48-fold) IP production, in human than in rat chondrocytes. The BK B₂ receptor antagonists MEN16132 and icatibant displayed similar binding affinity. MEN16132 was 40-fold more potent than icatibant in the IP assay. In human chondrocytes, BK increased release (over 24 h) of IL-6 and IL-8, effects blocked by MEN16132 but not by the B₁ receptor antagonist Lys-[Leu⁸][desArg⁹]BK. BK-induced release of IL-6, but not of IL-8, was partially inhibited by indomethacin (10 µM) and nordihydroguaiaretic acid (10 µM). Antagonists for the prostanoid EP receptors (AH6809 10 µM; L-798 196, 200 nM; L-161 982, 1 µM) were ineffective. Dexamethasone (100 nM) partially inhibited release of both IL-6 and IL-8. Inhibitors of intracellular downstream signalling pathways (SB203580 10 µM; PD98059, 30 µM; SP600125, 30 µM; BAY-117085, 5 µM) indicated the involvement of p38 MAPK and the activation of NF-κB.

CONCLUSION AND IMPLICATIONS

BK mediated inflammatory changes and cartilage degradation and B₂ receptor blockade would, therefore, be a potential treatment for OA.     

Correlation of the intrinsic clearance of donepezil (Aricept®) between in vivo and in vitro studies in rat,dog and human

1. Donepezil hydrochloride (Aricept®) is used for the treatment of Alzheimer's disease. Here the correlation of the intrinsic clearance (Cl_int) of donepezil between the in vivo and in vitro states was studied in rat, dog and human. 2. In an experiment with ¹⁴C-donepezil and human microsomes the routes of metabolism were identified as N-dealkylation and O-demethylation, and no unknown metabolites were detected. 3. The Cl_int of donepezil in the male rat, female rat, dog and human liver microsomes were 33.7, 13.4, 37.0 and 6.35 μl/min/mg microsomal protein respectively, and sex difference in rat and interspecies difference in the estimated Cl_int were found. 4. After a single intravenous administration to the male rat, female rat and dog, total plasma clearance (Cl^P_total) was 78.6, 29.5 and 88.3 ml/min/kg respectively, and a sex difference was observed in rat. 5. After a single oral administration to the male rat, dog and healthy volunteer, Cl^P_total/F was 140, 105 and 2.35 ml/min/kg respectively, and remarkable differences were observed between animals and man. 6. The contribution of renal clearance to blood clearance (Cl_r) was low in all species. The predicted in vitro hepatic clearance (Cl_h-pre) was in the rank order: male rat (15.91 ml/min/kg) > dog (7.96) > female rat (7.67) > human (1.04). Although Cl_h-pre was underestimated, Cl_h-pre was significantly correlated with that of ClBtotal in the different animal species and in man, indicating that the in vitro-in vivo ranking order was conserved.     

β-Naphthoflavone induced CYP1A1 and 1A3 proteins in the liver of rainbow trout (Oncorhynchus mykiss)

1. Two CYP1A proteins, designated HAP 1 andHAP 2, were isolated from the liver of the β-naphthoflavone(BNF)-treated rainbow trout. The proteins were initially resolved by chromatography on a DEAE sepharose column and were further purified by hydroxylapatite chromatography. 2. Both HAP 1 and HAP 2 proteins exhibited high 7-ethoxyresorufin, methoxy resorufin and phenacetin O-dealkylase activities and were good catalysts for the oxidation of 7,12-dimethylbenz[a]anthracene (DMBA). No qualitative difference was observed between the two proteins in their ability to catalyse the formation of the individual metabolites of DMBA. 3. The two purified proteins showed identical amino acid sequence for the first 13 amino acids. However, the 14th amino acid was valine for HAP 1 protein and alanine for HAP 2 protein. 4. Alignment ofthe amino acid sequences showed that HAP 1 protein was identical to the deduced protein ofthe previously reported troutCYP1A2 (renamed CYP1A1) gene for the first 24 amino acids at the N-terminal region. HAP 2 protein corresponded to the deduced protein sequence of CYP1A3 gene for the first 14 amino acids. However, unlike the deduced sequences of CYP1A1 and 1A3 the N -terminal methionine was absent in the purified proteins. 5. We conclude thatHAP 1 and HAP 2 are the products ofthe CYP1A1 and CYP1A3 genes respectively, and are found in the liver of the BNF-treated rainbow trout.     

Effect of γ-ray on metabolic enzyme CYP3A1 in rat liver on multiple levels北大核心CSCD

Aim To explore the effect of γ-ray on the mRNA,protein expression levels and metabolic activity level of the key drug metabolic enzyme CYP3A1 in rat liver. Methods Wistar rats were randomly divided into control group, 24 h post-radiation group and 72 h post-radiation group. The experimental group was exposed to total body irradiation of single 6 Gy γ-ray. Blood was collected from the orbital venous plexus for blood routine examination and biochemical analysis 24 h and 72 h after irradiation, and liver tissue was prepared for quantifying expression of CYP3A1 mRNA and liver-specific microRNA (miR-122-5p) through RT-PCR. The expression level of CYP3A1 protein was analyzed by Western blot, and the metabolic activity level of CYP3A1 detected by the specific substrate midazolam combined with LC-MS method. Results Com¬pared with the control group, the weights of the rats in the radiation group significantly decreased, and the number of white blood cells was markedly reduced. Simultaneously, the activities of alanine aminotrans-ferase and alkaline phosphatase continuously descended, as well as the levels of total bilirubin and bile acid significantly increased, which indicated that the liver may be damaged after radiation. The relative expression of CYP3A1 mRNA continued to increase significantly 24 h and 72 h after irradiation. CYP3A1 protein expression and metabolic activity levels showed an obvious increasing trend 24 h after irradiation, and rose significantly 72 h after irradiation compared with the control group. At the same time, the expression of miR-122-5p in liver of rats in the 24 h and 72 h post-radiation group continued to decrease rapidly compared with the control group. Conclusions γ-ray radiation may arouse damage effect on liver, which leads to the continuous up-regulation of the mRNA and protein expression levels of the capital metabolic enzyme CYP3A1 in liver tissue, as well as the elevation of the metabolic activity level. The regulatory mechanism might be related to miR-122-5p. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Bioavailability and disposition of ‘H-solanine in rat and hamster

1. The toxicokinetics of [³H]-α-solanine after oral (p.o.) and intravenous (i.v.) administration in rat and hamster were studied, in order to decide which is the most appropriate model in risk assessment studies. The i.v. Dose was 54 βg/kg; the oral dose was 170 βg/kg.

2. After i.v. Administration, the toxicokinetics of total radioactivity in blood were comparable in rat and hamster. However, the clearance of total radioactivity from plasma was more effective in rat than in hamster. The half-lives of distribution and of the terminal phase of unchanged α-solanine were not different between rat and hamster, whereas the systemic and metabolic clearance were, respectively, about 1.6 and 2.7 times higher in rat than in hamster. The clearance of unchanged α-solanine is more effective than of total radioactivity.

3. After p.o. Administration in rat and hamster, the mean bioavailability of total radioactivity is about 29 and 57%, respectively. The bioavailability of unchanged α-solanine is only 1.6 and 3.2%, respectively, when compared with i.v. administration.

4. T_1/2el of α-solanine after p.o. Administration was in rats a factor of four and in hamsters a factor of two shorter than after i.v. Administration. A strong retention of radioactivity was seen in the hamsters after p.o. Administration; only 40% of the dose was excreted within 7 days versus 90% in rat.

5. Based on these and toxicological data from literature, it was decided that the hamster is a more appropriate model in (sub) chronic toxicity studies with α-solanine than the rat.     

A comparison of the concentration–effect relationships of PAHs on CYP1A induction in HepG2 and Mcf7 cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants. Some compounds belonging to this group are considered carcinogenic to people. In order to yield carcinogenic properties, these compounds must be metabolically transformed by enzymes of cytochrome P450 family to oxy-derivatives. In this study, the ability of the following six PAHs: anthracene (Ant), benz(a)anthracene (BA), naphthacene (Nap), benzo(a)pyrene (BaP), dibenz(a,c)anthracene (DB(a,c)A) and dibenz(a,h)anthracene (DB(a,h)A) to induce enzymes of cytochrome P450 (CYP450), in particular CYP1A1 and CYP1A2 in Mcf7 and HepG2 cells was studied. The induction of CYP1A enzymes was assessed at the level of enzymatic protein and enzymatic activity. The change in CYP1A1 and CYP1A2 protein level was assessed by means of confocal microscopy. The ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-deethylase (MROD) assays were applied to determine the CYP1A1 and CYP1A2 activity. The Induction Equivalency Factors (IEFs) were also determined. According to EROD and MROD assay and calculated IEFs the following order of the inducing potency was determined in HepG2 cells: DB(a,h)A > BaP > DB(a,c)A ≈ BA > Nap > Ant, and in Mcf7 cells: DB(a,h)A > DB(a,c)A > BaP > Nap > BA > Ant. The assessment of the protein levels revealed that DB(a,h)A was also the strongest inducer of protein level, however the correlation between enzymatic activity and protein level induction by other PAHs was not always evident. The EROD and MROD activities were higher in Mcf7 than in HepG2 cells, however the CYP1A2 protein level was shown to be higher in HepG2 cells. The results obtained indicate possible catalytic enzymatic activity alterations induced by PAHs.     

α1A and α1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex

Summary We have studied the role of _1A and _1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [³H]Prazosin binding studies with and without inactivation of _1B-adrenoceptors by chloroethylclonidine treatment suggested that noradrenaline lacks relevant selectivity for ₁-adrenoceptor subtypes. Both agonists stimulated [³H]inositol phosphate accumulation with similar maximal effects. The _1A-selective antagonists 5-methyl-urapidil and (+)-niguldipine inhibited inositol phosphate formation by both agonists with shallow biphasic curves but the high affinity component was only 15%–31% and 38%–41%, respectively. The irreversible _1B-selective antagonist chloroethylclonidine inhibited inositol phosphate generation by both agonists by 54%–57%. In contrast to our previous data in rat cerebral cortical slices; we conclude that in rat renal cortex both _1A- and _1B-adrenoceptors are involved in noradrenaline-and methoxamine-stimulated inositol phosphate generation.     

Determination of caffeine and five metabolites simultaneously by HPLC and application on evaluating the activity of CYP1A2, CYP2A6, NAT2 and XO in Chinese healthy volunteers

HPLC同时检测咖啡因及其代谢产物并在健康中国人群中CYP1A2,CYP2A6,NATR和XO酶活性评价中的应用@陈尧$Pharmacogenetics Research Institute, Central South University!Changsha 410078, Hunan, China @欧阳冬生$Pharmacogenetics Research Institute, Central South Univer