title: Inhibition of human P450 enzymes by nicotinic acid and nicotinamide.
abstract: Nicotinic acid has been used as a cholesterol-lowering agent for a few decades already, whereas the cytoprotective and antiviral properties of nicotinamide are slowly gaining attention. In both cases however, very high doses are needed to achieve a therapeutic effect, resulting in blood concentrations sometimes as high as 15 mM. Based on their common pyridine functionality, we hypothesized that these two molecules could inhibit human P450 enzymes. In vitro inhibition studies demonstrate that, at their therapeutic concentrations, both nicotinic acid and nicotinamide inhibit CYP2D6 (Ki = 3.8 +/- 0.3 and 19 +/- 4 mM, respectively). Nicotinamide also inhibits CYP3A4 (Ki = 13 +/- 3 mM) and CYP2E1 (Ki = 13 +/- 8 mM). As expected for nitrogen-containing heteroaromatic molecules, spectrophotometric analysis indicates that the inhibition occurs via coordination of the pyridine nitrogen atom to the heme iron.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Que., Canada H3A 2K6.
authors.forename: Cédric
authors.initials: C
authors.lastname: Gaudineau
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009525:Niacin / Q000494:pharmacology*; D009536:Niacinamide / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009536:Niacinamide; D009525:Niacin