title: Role of cytochrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel-induced neurotoxicity.
abstract: OBJECTIVE
  The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel-induced neuropathy but the data hitherto published are conflicting.
  
  
  METHODS
  In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic properties of CYP2C8.3 variant were analyzed using heterologous mammalian HEK293 cell expression system.
  
  
  RESULTS
  No significant association between CYP2C8*3 allele and neuropathy was found, although a trend was observed. The paclitaxel and amodiaquine metabolism by CYP2C8.3 were found similar to CYP2C8.1, whereas CYP2C8.3 was more efficient in the metabolism of rosiglitazone.
  
  
  CONCLUSIONS
  These results indicate a difference in substrate specificity between CYP2C8.1 and CYP2C8.3; however, the CYP2C8*3 allele has no major impact on paclitaxel metabolism in vitro or of paclitaxel-induced neuropathy in vivo. Original submitted on 6 February 2015; revision submitted on 9 April 2015.
authors.affiliation: Section of Pharmacogenetics, Department of Physiology & Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Apellániz-Ruiz
authors.affiliation: Section of Pharmacogenetics, Department of Physiology & Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Johansson
authors.affiliation: Clinical Pharmacology, Division of Drug Research, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.affiliation: Research Unit of Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.affiliation: Research Unit of Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Clinical Pharmacology, Division of Drug Research, Faculty of Health Sciences, Linköping University, Linköping, Sweden.|Department of Forensic Genetics & Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Green
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.affiliation: Section of Pharmacogenetics, Department of Physiology & Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
mesh_terms: D000483:Alleles; D000655:Amodiaquine / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000453:epidemiology* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D017239:Paclitaxel / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000077154:Rosiglitazone; D013379:Substrate Specificity; D045162:Thiazolidinediones / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000655:Amodiaquine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel
keywords: CYP2C8; amodiaquine; breast cancer; neuropathy; ovarian cancer; paclitaxel; rosiglitazone