Fluorescencein situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1

Inoue, Kiyoshi; Inazawa, Johji; Suzuki, Yasuhiko; Shimada, Tsutomu; Yamazaki, Hiroshi; Guengerich, F. Peter; Abe, Tatsuo

doi:10.1007/bf01874052

Cited by 15 publications

(9 citation statements)

References 16 publications

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“…1. Expression levels of each of the CYP2C8 proteins exceeded the typical CYP2C content measured in human liver microsomes, estimated at 60 pmol P450/mg protein (Inoue et al, 1994), and were consistent with the levels of P450 expressed in E. coli described elsewhere Smith et al, 1998). The levels of P450 reductase expressed were slightly lower than the typical P450 (Forrester et al, 1992).…”

Section: Resultssupporting

confidence: 75%

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cisRetinoic Acid and Paclitaxel Hydroxylation

Rowbotham¹,

Boddy²,

Redfern³

et al. 2010

Drug Metab Dispos

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ABSTRACT:CYP2C8 has a major role in the metabolism of the anticancer agents 13-cis retinoic acid (13cisRA) and paclitaxel. There is evidence that polymorphisms in the CYP2C8 gene contribute to observed interindividual differences in paclitaxel metabolism. However, no studies have been performed to determine the relevance of CYP2C8 polymorphisms to 13cisRA metabolism. In the current study, the effect of two common nonsynonymous CYP2C8 polymorphisms, CYP2C8*3 (R139K and K399R) and *4 (I264M), on the metabolism of 13cisRA and paclitaxel was examined using an Escherichia coli expression system with coexpression of human cytochrome P450 reductase. No statistically significant differences in the level of 13cisRA 4-hydroxylase activity were associated with either CYP2C8 allelic variant compared with the wild-type CYP2C8.1 enzyme. Furthermore, no differences were observed for the CYP2C8.3 or CYP2C8.4 enzymes with respect to paclitaxel 6␣-hydroxylase kinetics compared with wild-type CYP2C8.1. However, when the effects of the individual polymorphisms making up the CYP2C8*3 allele were considered, a significantly lower level of paclitaxel 6␣-hydroxylase activity was associated with the K399R enzyme. A lower level of activity was also seen for the R139K enzyme, although this difference was not significant. No differences were observed with respect to 13cisRA 4-hydroxylase activity. We conclude that common CYP2C8 polymorphisms are unlikely to explain reported interindividual variation in 13cisRA or paclitaxel pharmacokinetics.Chemotherapy with 13-cis retinoic acid [(13cisRA) isotretinoin] is integral to the treatment of high-risk neuroblastoma (Matthay et al., 1999(Matthay et al., , 2009). Previous studies have demonstrated a high degree of interpatient variability in the pharmacokinetics and metabolism of 13cisRA . Thus, identification of factors predictive of 13cisRA pharmacokinetics and metabolism may allow the optimization of 13cisRA therapy.Several cytochromes P450 (P450s) have been reported to catalyze the oxidation of 13cisRA, including CYP3A7, 2C8, 4A11, 1B1, 2B6, 2C9, 2C19, and 3A4 Marill et al., 2002). Based on both hepatic expression and overall activity, CYP2C8 is considered to be a major isoform involved in 13cisRA metabolism. Indeed, CYP2C8 plays a major role in the metabolism of a number of therapeutically important drugs, and it is the principal enzyme responsible for the oxidative metabolism of the anticancer agent paclitaxel (Rahman et al., 1994). To date, sixteen CYP2C8 alleles have been described previously (www.cypalleles. ki.se), two of which, CYP2C8*3 and *4, include nonsynonymous polymorphisms commonly seen in whites (Dai et al., 2001;Bahadur et al., 2002;Henningsson et al., 2005). Both the *3 and *4 alleles have been associated with a lower rate of paclitaxel metabolism, based on in vitro approaches using expressed enzymes or liver microsomes, although not all studies agree on the extent of this effect (Dai et al., 2001;Soyama et al., 2001;Bahadur et al., 2002;Taniguchi et al., 2005;Parikh et al., 2...

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Section: Resultssupporting

confidence: 75%

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cisRetinoic Acid and Paclitaxel Hydroxylation

Rowbotham¹,

Boddy²,

Redfern³

et al. 2010

Drug Metab Dispos

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“…In a recent publication by Yajima et al (2014), in which the standard 2D hepatocyte culture model was used, of the eight hepatocyte lots treated with rifampin, CYP2C8 and CYP2C9 mRNA were not induced in five and two hepatocyte lots, respectively. This can be problematic given that both the European Medicines Agency and the Food and Drug Administration Regulatory Guidances now recommend that the CYP2C-induction-based DDI risk of NCEs need to be evaluated given that CYP2C comprises approximately 20% of total P450 content in human livers (Inoue et al, 1994) and that CYP2Cs are responsible for metabolizing approximately 20% of all prescribed drugs, including tolbutamide, phenytoin, warfarin, and ibuprofen (Goldstein, 2001).…”

Section: Introductionmentioning

confidence: 99%

Application of Micropatterned Cocultured Hepatocytes to Evaluate the Inductive Potential and Degradation Rate of Major Xenobiotic Metabolizing Enzymes

Dixit

Moore

Tsao

et al. 2015

Drug Metabolism and Disposition

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Long-term coculture models of hepatocytes are promising tools to study drug transport, clearance, and hepatoxicity. In this report we compare the basal expression of drug disposition genes and the inductive response of prototypical inducers (rifampin, phenobarbital, phenytoin) in hepatocyte two-dimensional monocultures and the long-term coculture model (HepatoPac). All the inducers used in the study increased the expression and activity of CYP3A4, CYP2B6 and CYP2C enzymes in the HepatoPac cultures. The coculture model showed a consistent and higher induction of CYP2C enzymes compared with the monocultures. The EC 50 of rifampin for CYP3A4 and CYP2C9 was up to 10-fold lower in HepatoPac than the monocultures. The EC 50 of rifampin calculated from the clinical drug interaction studies correlated well with the EC 50 observed in the HepatoPac cultures. Owing to the long-term stability of the HepatoPac cultures, we were able to directly measure a half-life (t 1/2 ) for both CYP3A4 and CYP2B6 using the depletion kinetics of mRNA and functional activity. The t 1/2 for CYP3A4 mRNA was 26 hours and that for the functional protein was 49 hours. The t 1/2 of CYP2B6 was 38 hours (mRNA) and 68 hours (activity), which is longer than CYP3A4 and shows the differential turnover of these two proteins. This is the first study to our knowledge to report the turnover rate of CYP2B6 in human hepatocytes. The data presented here demonstrate that the HepatoPac cultures have the potential to be used in long-term culture to mimic complex clinical scenarios.

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“…In humans, the CYP2C subfamily of cytochrome P450 enzymes, consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2C18, is an important subfamily of drug-metabolizing enzymes responsible for the metabolism of ϳ20% of all clinically prescribed therapeutic agents (Goldstein, 2001). They are found at highest levels in human liver (Goldstein and de Morais, 1994;Inoue et al, 1994;Klose et al, 1999;Nishimura et al, 2003), but CYP2C protein and/or mRNA expression has been detected at lower levels in extrahepatic tissues such as kidney, lung, heart, endothelial tissue, adrenal gland, mammary gland, and brain (McFayden et al, 1998;Klose et al, 1999;Nishimura et al, 2003;Yasar et al, 2003;Delozier et al, 2007;Deng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Human CYP2C8 Is Post-Transcriptionally Regulated by MicroRNAs 103 and 107 in Human Liver

et al. 2012

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Fluorescencein situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1

Cited by 15 publications

References 16 publications

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cisRetinoic Acid and Paclitaxel Hydroxylation

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cisRetinoic Acid and Paclitaxel Hydroxylation

Application of Micropatterned Cocultured Hepatocytes to Evaluate the Inductive Potential and Degradation Rate of Major Xenobiotic Metabolizing Enzymes

Human CYP2C8 Is Post-Transcriptionally Regulated by MicroRNAs 103 and 107 in Human Liver

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