Shimada, T., Yamazake, H., Mimura, M., Inui, Y. & Guengerich, F.P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270, 414−423
ABSTRACT Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 (about 4%), 2D6 (about 2%) and 2B6 (< 1%) were the minor P-450 forms. Differences in some of the P-450 1A2-, 2A6-, 2D6-, 2E1- and 3A4-dependent activities were observed in Japanese and Caucasian populations. No clear sex-related differences in individual P-450 contents and drug- and carcinogen-metabolizing activities were detected in 60 human samples, except that P-450 1A2-dependent activities were found to be higher in mean than in women in the Caucasian population only. A single neonate sample tended to be lower in P-450 1A2-, 2A6- and 2E1-dependent activities. In contrast to rat counterparts, we could not detect apparent developmental changes in P-450 content and activity in humans between 12 and 73 years old. Thus, the results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.
- SourceAvailable from: Anton J M Loonen
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- "However, specifi c xenobiotics are usually substrates of several CYP isoforms. Because CYP2D6 and CYP1A2 account for about 2 and 13%, respectively of the total CYP content in the human liver (Shimada et al. 1994), it has been suggested that CYP2D6 can be considered a high-affi nity, but low-capacity metabolic clearance pathway for most typical antipsychotic drugs, whereas CYP1A2 would be a low-affi nity, high-capacity metabolic clearance pathway (Fu et al. 2006). An important characteristic of CYP1A2 is its inducibility by several drugs, coffee consumption and tobacco smoking (Mookhoek and Loonen 2004; Flockhart 2007). "
ABSTRACT: Objectives. The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>А, rs762551) polymorphism in Russian psychiatric inpatients. Methods. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1-4 and 5-7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes. Results. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (-163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5-7 score than those with the A/C or the A/A genotype. Conclusions. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism.The World Journal of Biological Psychiatry 01/2015; 16(3):1-6. DOI:10.3109/15622975.2014.995222 · 4.23 Impact Factor
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- "Identification of key biotransformation pathways and responsible enyzmes (reaction phenotyping) are typically determined using in vitro model systems such as human liver microsomes (HLM), recombinant enzymes, hepatocytes, etc. Cytochrome P450 enzymes are recognized as clinically relevant for xenobiotics metabolism. Human liver contains most abundantly CYP3A4, although the levels can vary significantly (>10-fold) among individuals (Shimada et al., 1994; Yeo et al., 2004). The CYP3A subfamily plays a predominant role in the metabolism of drugs (Guengerich, 1996). "
ABSTRACT: 1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ945) is a small molecule inhibitor of CSF-1R kinase activity within osteoclasts designed to prevent skeletal related events in metastatic disease. Key metabolites were enzymatically and structurally characterized to understand the metabolic fate of BLZ945 and pharmacological implications. The relative intrinsic clearances for metabolites were derived from in vitro studies using human hepatocytes, microsomes and phenotyped with recombinant P450 enzymes. 2. Formation of a pharmacologically active metabolite (M9) was observed in human hepatocytes. The M9 metabolite is a structural isomer (diastereomer) of BLZ945 and is about 4-fold less potent. This isomer was enzymatically formed via P450 oxidation of the BLZ945 hydroxyl group, followed by aldo–keto reduction to the alcohol (M9). 3. Two reaction phenotyping approaches based on fractional clearances were applied to BLZ945 using hepatocytes and liver microsomes. The fraction metabolized (fm) or contribution ratio was determined for each metabolic reaction type (oxidation, glucuronidation or isomerization) as well as for each metabolite. The results quantitatively illustrate contribution ratios of the involved enzymes and pathways, e.g. the isomerization to metabolite M9 accounted for 24% intrinsic clearance in human hepatocytes. In summary, contribution ratios for the Phase I and Phase II pathways can be determined in hepatocytes.Xenobiotica 09/2014; 45(2). DOI:10.3109/00498254.2014.945988 · 2.10 Impact Factor
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- "Among the CYP families, CYP1, CYP2, and CYP3 are most relevant for human drug metabolism and are responsible for the biotransformation of a large proportion of the commonly prescribed drugs in the United States (Venkatakrishnan et al. 2001; Zlokarnik et al. 2005). A large number of marketed drugs are metabolized by CYP1A2, CYP2D6, and CYP3A4 (Shimada et al. 1994; Nelson et al. 1996; Hellum et al. 2006). CYP1A2 represents about 13% CYP enzymes in the human liver and is involved in the metabolism of acetaminophen, clomipramine, and imipramine (Yan and Caldwell 2001). "
ABSTRACT: A multiplex RT-qPCR was developed to examine CYP1A2, CYP2D6, and CYP3A4 induction properties of compounds from food and herbal sources. The induction of drug metabolizing enzymes is an important pharmacokinetic interaction with unique features in comparison with inhibition of metabolizing enzymes. Cyto-chrome induction can lead to serious drug–drug or drug–food interactions, espe-cially if the coadministered drug plasma level is critical as it can reduce therapeutic effects and cause complications. Using this optimized multiplex RT-qPCR, cytochrome induction properties of andrographolide, curcumin, lyco-pene, bergamottin, and resveratrol were determined. Andrographolide, curcumin, and lycopene produced no significant induction effects on CYP1A2, CYP2D6, and CYP3A4. However, bergamottin appeared to be a significant in vitro CYP1A2 inducer starting from 5 to 50 lmol/L with induction ranging from 60 to 100-fold changes. On the other hand, resveratrol is a weak in vitro CYP1A2 inducer. Exam-ining the cytochrome induction properties of food and herbal compounds help complement CYP inhibition studies and provide labeling and safety caution for such products.Food Science & Nutrition 09/2014; 2(5). DOI:10.1002/fsn3.122