Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Evidence of significant contribution from CYP3A5 to hepatic drug metabolism.

Authors: Huang, Weili; Lin, Yvonne S; McConn 2nd, Donavon J; Calamia, Justina C; Totah, Rheem A; Isoherranen, Nina; Glodowski, Mary; Thummel, Kenneth E

Published In Drug Metab Dispos, (2004 Dec)

Abstract: CYP3A4 and CYP3A5 exhibit significant overlap in substrate specificity but can differ in product regioselectivity and formation activity. To further explore this issue, we compared the kinetics of product formation for eight different substrates, using heterologously expressed CYP3A4 and CYP3A5 and phenotyped human liver microsomes. Both enzymes displayed allosteric behavior toward six of the substrates. When it occurred, the "maximal" intrinsic clearance was used for quantitative comparisons. Based on this parameter, CYP3A5 was more active than CYP3A4 in catalyzing total midazolam hydroxylation (3-fold) and lidocaine demethylation (1.4-fold). CYP3A5 exhibited comparable metabolic activity as CYP3A4 (90-110%) toward dextromethorphan N-demethylation and carbamazepine epoxidation. CYP3A5-catalyzed erythromycin N-demethylation, total flunitrazepam hydroxylation, testosterone 6beta-hydroxylation, and terfenadine alcohol formation occurred with an intrinsic clearance that was less than 65% that of CYP3A4. Using two sets of human liver microsomes with equivalent CYP3A4-specific content but markedly different CYP3A5 content (group 1, predominantly CYP3A4; group 2, CYP3A4 + CYP3A5), we assessed the contribution of CYP3A5 to product formation rates determined at low substrate concentrations (< or = Km). Mean product formation rates for group 2 microsomes were 1.4- to 2.2-fold higher than those of group 1 (p < 0.05 for 5 of 8 substrates). After adjusting for CYP3A4 activity (itraconazole hydroxylation), mean product formation rates for group 2 microsomes were still significantly higher than those of group 1 (p < 0.05 for 3 substrates). We suggest that, under conditions when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool, the contribution of CYP3A5 to the clearance of some drugs may be an important source of interindividual variability.

PubMed ID: 15383492 Exiting the NIEHS site

MeSH Terms: Animals; Antifungal Agents/metabolism; Baculoviridae; Biotransformation; Cell Line; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System/biosynthesis; Cytochrome P-450 Enzyme System/metabolism*; Cytochromes b5/biosynthesis; Cytochromes b5/metabolism; Flunitrazepam/metabolism; Humans; In Vitro Techniques; Insecta; Isoenzymes/metabolism; Itraconazole/metabolism; Kinetics; Liver/enzymology; Liver/metabolism*; Microsomes, Liver/enzymology; Midazolam/metabolism; Pharmaceutical Preparations/metabolism*

Back
to Top