Abstract

The P450 26 family is believed to be responsible for retinoic acid (RA) metabolism and elimination in the human fetus and adults. CYP26A1 and CYP26B1 mRNA is expressed in tissue specific manner and knockout mice of the CYP26 isoforms show distinct malformations and lethality. The aim of this study was to determine differences in CYP26A1 and CYP26B1 regulation and expression. Analysis of CYP26A1 and CYP26B1 expression in a panel of 57 human livers showed CYP26A1 being the major CYP26 isoform present in the liver and its expression being subject to large inter-individual variability between donors. CYP26A1 and RARβ were found to be greatly inducible by RA in HepG2 cells, whereas CYP26B1, RARα and RARγ induced to a much lesser extent. Based on treatments with RAR isoform selective ligands, RARα is the major isoform responsible for CYP26A1 and RARβ induction in HepG2 cells. Classical P450 inducers did not affect CYP26 transcription whereas PPARγ agonists, pioglitazone and rosiglitazone, up-regulated CYP26B1 transcription by as much as 209 ± 80-fold and CYP26A1 by 10-fold. RARβ was also up-regulated by pioglitazone and rosiglitazone. CYP26B1 induction by PPARγ agonists was abolished by the irreversible PPARγ antagonist (GW9662) whereas RARβ and CYP26A1 induction was unaffected by GW9662. Overall, the results of this study suggest that CYP26B1 and CYP26A1 are regulated by different nuclear receptors resulting in tissue specific expression patterns. The fact that drugs can alter the expression of CYP26 enzymes may have toxicological and therapeutic importance.