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CYP1A2 Activity (cyp1a2 + activity)
Selected AbstractsAssessment of CYP1A2 Activity in Clinical Practice: Why, How, and When?BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2005Mirko S. Faber CYP1A2 activity shows both pronounced intra- and interindividual variability, which is, among other factors, related to smoking causing enzyme induction, to drug intake and to dietary factors which may result in induction or inhibition. In contrast to these exogenous factors, genetic influences on enzyme activity seem to be less pronounced. Therefore, phenotyping of CYP1A2, i.e. the determination of the actual activity of the enzyme in vivo, represents a useful approach both for scientific and clinical applications. CYP1A2 is almost exclusively expressed in the liver. Since liver tissue cannot be obtained for direct phenotyping, a probe drug which is metabolized by CYP1A2 has to be given. Proposed probe drugs include caffeine, theophylline, and melatonin. Caffeine is most often used because of the predominating role of CYP1A2 in its overall metabolism and the excellent tolerability. Various urinary, plasma, saliva, and breath based CYP1A2 caffeine metrics have been applied. While caffeine clearance is considered as the gold standard, the salivary or plasma ratio of paraxanthine to caffeine in a sample taken approximately 6 hr after a defined dose of caffeine is a more convenient, less expensive but also fully validated CYP1A2 phenotyping metric. CYP1A2 phenotyping is applied frequently in epidemiologic and drug-drug interaction studies, but its clinical use and usefulness remains to be established. [source] Sulforaphane and its analogues inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyreneJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2009Katarzyna Skupinska Abstract CYP1A1 and CYP1A2 enzymes metabolize polycyclic aromatic hydrocarbons (PAHs) to the reactive oxyderivatives. PAHs can induce the activity of both enzymes, which increases its conversion and enhances risk of carcinogenesis. Thus, the inhibition of CYP enzymes is recognized as a cancer chemoprevention strategy. A well-known group of chemopreventive agents is isothiocyanates, which occur naturally in Brassica vegetables. In this paper, a naturally occurring sulforaphane and its two synthetic analogues isothiocyanate-2-oxohexyl and alyssin were investigated. The aim of the study was to determine whether the differences in the isothiocyanate structure change its ability to inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyrene in HepG2 and Mcf7 cells. Also a mechanistic study was performed including isothiocyanates' influence on CYP1A1 and CYP1A2 catalytic activity, enzymatic protein level, and AhR translocation. It was shown that both enzymes were significantly induced by benzo[a]pyrene, and isothiocyanates were capable of decreasing the induced activity. The inhibitory properties depend on the types of isothiocyanate and enzyme. In general, CYP1A2 was altered in the more meaningful way than CYP1A1 by isothiocyanates. Sulforaphane exhibited weak inhibitory properties, whereas both analogues were capable of inhibiting BaP-induced activity with the similar efficacy. The mechanistic study revealed that analogues decreased the CYP1A2 activity via the protein-level reduction and CYP1A1 directly. The results indicate that isothiocyanates can be considered as potent chemopreventive substances and the change in the sulforaphane structure increases its chemopreventive potency. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:18,28, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20259 [source] Effect of herbal teas on hepatic drug metabolizing enzymes in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2001Pius P. Maliakal We have investigated the effect of herbal teas (peppermint, chamomile and dandelion) on the activity of hepatic phase I and phase II metabolizing enzymes using rat liver microsomes. Female Wistar rats were divided into six groups (n = 5 each). Three groups had free access to a tea solution (2 %) while the control group had water. Two groups received either green tea extract (0.1 %) or aqueous caffeine solution (0.0625 %). After four weeks of pretreatment, different cytochrome P450 (CYP) isoforms and phase II enzyme activities were determined by incubation of liver microsomes or cytosol with appropriate substrates. Activity of CYP1A2 in the liver microsomes of rats receiving dandelion, peppermint or chamomile tea was significantly decreased (P < 0.05) to 15 %, 24 % and 39 % of the control value, respectively. CYP1A2 activity was significantly increased by pretreatment with caffeine solution. No alterations were observed in the activities of CYP2D and CYP3A in any group of the pretreated rats. Activity of CYP2E in rats receiving dandelion or peppermint tea was significantly lower than in the control group, 48 % and 60 % of the control, respectively. There was a dramatic increase (244 % of control) in the activity of phase II detoxifying enzyme UDP-glucuronosyl transferase in the dandelion tea-pretreated group. There was no change in the activity of glutathione-S-transferase. The results suggested that, like green and black teas, certain herbal teas can cause modulation of phase I and phase II drug metabolizing enzymes. [source] Inhibitory effect of magnolol on Trp-P-2-induced DNA damage in various organs in micePHYTOTHERAPY RESEARCH, Issue 7 2009Junichiro Saito Abstract Magnolol has been reported to strongly inhibit the mutagenicity induced by indirect mutagens in the Ames test as well as the clastogenicity induced by benzo(a)pyrene (B(a)P) in the mice micronucleus test. Here, we evaluated the inhibitory effect of magnolol on the DNA damage induced by 3-amino-1-methyl-5H -pyrido[4,3-b]indole (Trp-P-2) in various organs using the mice alkaline single cell gel electrophoresis (SCG) assay. Animals were treated with a single oral administration of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg), followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). The liver, lung, and kidney were removed at 3 h after treatment and used in SCG assay. The results indicated that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate the mechanism of this inhibitory effect against Trp-P-2, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using the zoxazolamine paralysis test. Magnolol significantly prolonged zoxazolamine paralysis time and showed an inhibitory effect on in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on the DNA damage induced by Trp-P-2 in various organs in vivo. This inhibitory mechanism is considered due to in vivo CYP1A2 inhibition. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effects of Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix Extracts on Cytochrome P450 Activities in Healthy VolunteersBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009SoJeong Yi A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05,0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54,0.94). In addition, S. radix showed a 1.42-fold (1.03,1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings. [source] Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Janne T. Backman Aims Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. Methods In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. Results Rofecoxib increased the area under the plasma concentration,time curve (AUC0,,) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC0,25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). Conclusions Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs. [source] The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant womenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2002Anna Nordmark Aims, To investigate the influence of the CYP1A2*1F mutation on CYP1A2 activity in smoking and nonsmoking pregnant women. Methods Pregnant women (n = 904) who served as control subjects in a case-control study of early fetal loss were investigated. They were phenotyped for CYP1A2 using dietary caffeine and the urinary ratio AFMU + 1X + 1 U/1,7 U. An assay for CYP1A2*1F using 5,-nuclease assay (Taqman) was developed to genotype the population. Results, The frequencies of *1 A and *1F alleles among Swedish women were 0.29 and 0.71, respectively. There was no statistically significant difference in CYP1A2 activity between the genotypes, although a trend towards enhanced activity was observed in *1F/*1F (log MRc 0.77) and *1F/*1 A (log MRc 0.82) genotypes compared with the *1 A/*1 A genotype (log MRc 0.71) (anovaP = 0.07). The mean difference between the *1 A homozygotes and the heterozygotes was 0.11 [95% confidence interval of the difference: (,0.21, ,0.01)] and that between the *1 A and *1F homozygotes was 0.05 [95% confidence interval of the difference: (,0.13, 0.03)]. No significant effect (P = 0.22) of the *1F on CYP1A2 activity was observed in smokers, tested using an interaction term (smoking * genotype) in the anova model (*1F/*1F log MRc 0.79, *1F/*1 A log MRc 0.86, and *1 A/*1 A log MRc 0.73). In smokers, there was no difference in ratio between homozygotes for the *1 A and *1F alleles [mean difference ,0.06; 95% confidence interval of the difference: ,0.22, 0.11] or between *1 A/*1 A and *1 A/*1F genotypes [mean difference ,0.13; 95% confidence interval of the difference: ,0.29, 0.04]. Conclusions, The effect of the CYP1A2*1F mutation on CYP1A2 activity in smoking pregnant women could not be confirmed. [source] CYP1A2 polymorphism (C,>,A at position ,163) in Ovambos, Koreans and MongoliansCELL BIOCHEMISTRY AND FUNCTION, Issue 5 2007Junko Fujihara Abstract Cytochrome P450 1A2 (CYP1A2) plays an important role in metabolizing drugs and xenobiotics, and is a possible participant in the development of several human diseases. Recent studies have shown that genetic polymorphism of ,163 C,>,A single nucleotide mutation of CYP1A2 increases the risk of myocardial infarction and modulates CYP1A2 activity. In this study, we investigated the frequency of the ,163 C,>,A mutation in Ovambos (n,=,177), Koreans (n,=,250) and Mongolians (n,=,153) and compared our results with other studies. Detection of this single nucleotide polymorphism was by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The frequencies of mutation (CYP1A2*,163A) in the Ovambos, Koreans and Mongolians were 0.46, 0.32 and 0.21, respectively. Ovambos showed a relatively higher frequency of mutation, similar to that of Tanzanians, while the Mongolians showed the lowest frequency of all study groups, including those from previous studies. This study is the first to investigate the distribution of the CYP1A2 (,163 C,>,A single nucleotide polymorphism) mutant allele in Ovambo, Korean and Mongolian populations. Copyright © 2006 John Wiley & Sons, Ltd. [source] | ||||||||||