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 Ki 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 kinact/KI 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.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Ikemura N,Yamaori S,Kobayashi C,Kamijo S,Murayama N,Yamazaki H,Ohmori Sdoi
10.1016/j.cbi.2019.04.005subject
Has Abstractpub_date
2019-06-01 00:00:00pages
1-9eissn
0009-2797issn
1872-7786pii
S0009-2797(19)30363-1journal_volume
306pub_type
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