Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine. (1st June 2019)

• Record Type: Journal Article
• Authors: Ikemura, Noriaki; Yamaori, Satoshi; Kobayashi, Chinatsu; Kamijo, Shinobu; Murayama, Norie; Yamazaki, Hiroshi; Ohmori, Shigeru
• Is Part Of: Chemico-biological interactions. Volume 306(2019)
• Page Start: 1
• Page End: 9
• Publication Date: 2019-06-01
• Subjects: Cytochrome P450 2J2 -- Antihypertensive drugs -- Inhibition -- Inactivation -- Docking simulation; ACEI angiotensin-converting enzyme inhibitor -- ARB angiotensin II receptor blocker -- CYP cytochrome P450 -- DCCB dihydropyridine calcium channel blocker -- EET epoxyeicosatrienoic acid -- KI half-maximal inhibitory concentration -- kinact maximal inactivation rate constant -- kobs observed rate of inactivation -- TKI tyrosine kinase inhibitor -- VEGF vascular endothelial growth factor; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.04.005
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: The inhibitory effects of antihypertensive drugs (dihydropyridine calcium channel blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors) on cytochrome P450 2J2 (CYP2J2) activity were examined. Amlodipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, telmisartan, delapril, and quinapril inhibited luciferin-2J2/4F12 O -dealkylase activity of recombinant human CYP2J2 in a concentration-dependent manner (IC50 = 0.116–9.19 μM). Kinetic analyses of the inhibition indicated that azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, manidipine, nicardipine, telmisartan, delapril, and quinapril competitively inhibited CYP2J2 activity, while amlodipine, felodipine, nifedipine, nilvadipine, nisoldipine, and nitrendipine showed mixed inhibition. Among these drugs, manidipine showed the strongest reversible inhibition with K i value of 0.0294 μM. The docking simulation data supported the potent inhibition of CYP2J2 by these drugs. Next, the effect of preincubation on CYP2J2 inhibition was investigated to determine whether these antihypertensive drugs inhibited CYP2J2 activity in a metabolism-dependent manner. A 20-min preincubation of azelnidipine and felodipine in the presence of NADPH potentiated the inhibition of CYP2J2. Furthermore, kinetic analysis of the inactivation showed that azelnidipine caused a preincubation time- and concentration-dependent decrease in CYP2J2 activity yielding k inact / K I value of 105 l/mmol/min, although felodipine showed no preincubation time-dependent inhibition. The azelnidipine-mediated inactivation required NADPH. These results indicated that manidipine is a potent competitive reversible inhibitor while azelnidipine is a potent mechanism-based inactivator of human CYP2J2. Highlights: Manidipine is a potent competitive reversible inhibitor of CYP2J2. Azelnidipine acts as a potent mechanism-based inhibitor of CYP2J2. Chemical inhibition of intratumoral CYP2J2 is a novel strategy for chemotherapy.