Identification of human cytochrome P450 isoforms that contribute to all-trans-retinoic acid 4-hydroxylation - PubMed (original) (raw)
Identification of human cytochrome P450 isoforms that contribute to all-trans-retinoic acid 4-hydroxylation
L C McSorley et al. Biochem Pharmacol. 2000.
Abstract
The role of specific human cytochrome P450 (CYP) isoforms in the oxidative metabolism of all-trans-retinoic acid was investigated by studies in human liver microsomes using isoform-specific chemical inhibitors and inhibitory antibodies. Studies using individual isoforms expressed in lymphoblastoid cells and correlation analysis using different microsome preparations were also performed. With expressed isoforms, evidence for a role for CYP2C8, CYP3A4, CYP2C9, and CYP1A1 in 4-hydroxylation was obtained, with the highest catalytic efficiency being observed for CYP2C8. Using inhibition studies and correlation analysis, we also concluded that CYP2C8 was the major all-trans-retinoic acid 4-hydroxylating cytochrome P450 in human liver microsomes, though CYP3A4 and, to a lesser extent CYP2C9, also made a contribution. In addition, we compared the rate of retinoic acid degredation in HepG2 cells when cultured in the absence and presence of 3-methylcholanthrene or all-trans-retinoic acid. Culture in the presence of all-trans-retinoic acid decreased the half-life twofold and resulted in an increased sensitivity of retinoic acid degredation to ketoconazole. Since no induction of either CYP1A1, CYP2C8, CYP2C9, or CYP3A4 was detected using immunoblotting and as mRNA encoding another cytochrome P450 enzyme, CYP26, has been previously demonstrated to be induced by retinoic acid treatment of HepG2 cells and to be highly sensitive to ketoconazole, this enzyme in addition to CYP2C8, CYP2C9 and CYP3A4 likely plays a role in all-trans-retinoic acid oxidation in the liver at high retinoic acid levels.
Similar articles
- Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone.
Baldwin SJ, Clarke SE, Chenery RJ. Baldwin SJ, et al. Br J Clin Pharmacol. 1999 Sep;48(3):424-32. doi: 10.1046/j.1365-2125.1999.00030.x. Br J Clin Pharmacol. 1999. PMID: 10510156 Free PMC article. - The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes.
He N, Edeki T. He N, et al. Am J Ther. 2004 May-Jun;11(3):206-12. doi: 10.1097/00045391-200405000-00009. Am J Ther. 2004. PMID: 15133536 Review. - Human cytochrome P450s: selectivity and measurement in vivo.
Smith DA, Abel SM, Hyland R, Jones BC. Smith DA, et al. Xenobiotica. 1998 Dec;28(12):1095-128. doi: 10.1080/004982598238859. Xenobiotica. 1998. PMID: 9890156 Review. No abstract available.
Cited by
- Development and validation of CYP26A1 inhibition assay for high-throughput screening.
Sakamuru S, Ma D, Pierro JD, Baker NC, Kleinstreuer N, Cali JJ, Knudsen TB, Xia M. Sakamuru S, et al. Biotechnol J. 2024 Jun;19(6):e2300659. doi: 10.1002/biot.202300659. Biotechnol J. 2024. PMID: 38863121 - Computational model for fetal skeletal defects potentially linked to disruption of retinoic acid signaling.
Pierro JD, Ahir BK, Baker NC, Kleinstreuer NC, Xia M, Knudsen TB. Pierro JD, et al. Front Pharmacol. 2022 Sep 6;13:971296. doi: 10.3389/fphar.2022.971296. eCollection 2022. Front Pharmacol. 2022. PMID: 36172177 Free PMC article. - The Roles of Four Novel P450 Genes in Pesticides Resistance in Apis cerana cerana Fabricius: Expression Levels and Detoxification Efficiency.
Zhang W, Yao Y, Wang H, Liu Z, Ma L, Wang Y, Xu B. Zhang W, et al. Front Genet. 2019 Nov 15;10:1000. doi: 10.3389/fgene.2019.01000. eCollection 2019. Front Genet. 2019. PMID: 31803222 Free PMC article. - Imidazoles as potential anticancer agents.
Ali I, Lone MN, Aboul-Enein HY. Ali I, et al. Medchemcomm. 2017 Apr 13;8(9):1742-1773. doi: 10.1039/c7md00067g. eCollection 2017 Sep 1. Medchemcomm. 2017. PMID: 30108886 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases