title: Overexpression of CYP3A5 attenuates inducibility and activity of CYP3A4 in HepG2 cells.
abstract: There have been conflicting reports regarding the catalytic role of cytochrome P450 (CYP)3A5, which range from deeming it irrelevant to suggesting it is equally as important as CYP3A4, the most potent and abundant catalytic cytochrome enzyme in the human liver. This was partially attributed to the fact that CYP3A5 is highly polymorphic. However the importance of other underlying mechanisms remain unclear. The aim of the present study was to investigate the interaction between these enzymes. A human HepG2 hepatocellular line stably overexpressing CYP3A5 was constructed. The results suggested that CYP3A5 does not affect CYP3A4 expression directly. However, overexpression of CYP3A5 attenuated the inducibility of CYP3A4 in response to dexamethasone. A luciferase reporter assay indicated that this attenuation was due to a decrease in CYP3A4 promoter activity. Furthermore, a pharmacokinetic assay using quinidine and amlodipine showed that CYP3A4 enzyme activity per mg of microsomal protein was also decreased in the group overexpressing CYP3A5 compared with the dexamethasone‑induced control group. In conclusion, the current study demonstrated that CYP3A5 may affect CYP3A4 at the transcriptional level and may thus modify CYP3A4 expression and activity in the presence of substrates and inducers. The results indicate that CYPs may interact with each other under certain conditions and that this interaction may be a novel mechanism by which drug‑drug interactions are mediated.
authors.affiliation: Department of Hypertension, Beijing Anzhen Hospital of Capital Medical University, Beijing 100029, P.R. China.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Geriatrics, The First Hospital, Peking University, Beijing 100034, P.R. China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Liu
authors.affiliation: Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes; D011401:Promoter Regions, Genetic
chemical_list: D007527:Isoenzymes; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A