In vitro inhibitory effects of components from Salvia miltiorrhiza on catalytic activity of three human AA ω-hydroxylases

Abstract CYP4 enzymes are involved in the metabolism of xenobiotics and endogenous molecules. 20-Hydroxyeicosatetraenoic acid (20-HETE), the arachidonic acid(AA) ω-hydroxylation metabolite catalyzed by CYP4A/4F enzymes, is implicated in various biological functions. The goal of this investigation is to examine the inhibitory effects of components from Salvia miltiorrhiza(Danshen) on AA ω-hydroxylation using recombinant CYP4A11, CYP4F2, CYP4F3B, and microsomal systems. Tanshinone IIA had noncompetitive inhibition on CYP4F3B(Ki = 4.98 μM). Cryptotanshinone(Ki = 6.87 μM) and tanshinone I (Ki = 0.42 μM) had mixed-type inhibition on CYP4A11. Dihydrotanshinone I had mixed-type inhibition on CYP4A11(Ki = 0.09 μM), and noncompetitive inhibition on CYP4F2(Ki = 4.25 μM) and CYP4F3B(Ki = 3.08 μM). Salvianolic acid A had competitive inhibition on CYP4A11 (Ki = 19.37 μM), and noncompetitive inhibition on CYP4F2(Ki = 15.28 μM) and CYP4F3B(Ki = 6.45 μM). Salvianolic acid C had noncompetitive inhibition on CYP4F2(Ki = 5.70 μM) and CYP4F3B (Ki = 18.64 μM). In human kidney, human liver or rat heart microsomes, 20-HETE formation was significantly inhibited (P