title: Human liver expression of CYP2C8: gender, age, and genotype effects.
abstract: Research investigating CYP2C8 as a drug-metabolizing enzyme has gained momentum over the past few years. CYP2C8 is estimated to oxidatively metabolize approximately 5% of therapeutically prescribed drugs. It is polymorphically expressed, and several single nucleotide polymorphisms have been identified with varying effects on the clearance of CYP2C8 substrates. However, the human liver expression of CYP2C8 and effects of genetic variation, age, and gender on mRNA and protein levels have not been fully explored. In this report, interindividual variation in CYP2C8 mRNA and protein expression in 60 livers from white individuals was examined. The livers were genotyped for CYP2C8*3 and CYP2C8*4 polymorphisms. The effects of genotype, age, and gender on hepatic CYP2C8 expression and the correlation of CYP2C8 mRNA expression with CYP3A4 and other CYP2C members were evaluated. The mean +/- S.D. protein levels in CYP2C8*1/*1 livers was 30.8 +/- 17.5 pmol/mg protein, and a trend for decreased protein levels was observed for CYP2C8*1/*4 livers (15.8 +/- 9.7 pmol/mg, p = 0.07). The mean expression levels of CYP2C8 was comparable in males and females (p = 0.18). The mRNA expression of CYP2C8, CYP2C9, CYP2C19, and CYP3A4, but not CYP2C18, was highly correlated (p < 0.0001). Moreover, the hepatic CYP2C8 and CYP3A4 protein levels were strongly correlated (r = 0.76, p < 0.0001). This correlation is most likely due to common regulation factors for both genes. CYP2C8 mRNA or protein expression levels were not significantly affected by CYP2C8*3 or *4 genotype, gender, or age, and variation observed clinically in CYP2C8 activity warrants further investigation.
authors.affiliation: Departments of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610, USA.
authors.forename: Suresh Babu
authors.initials: SB
authors.lastname: Naraharisetti
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Marciante
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Rheem A
authors.initials: RA
authors.lastname: Totah
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System