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 < 0.05) by dihydrotanshinone I (5 and 20 μM) and salvianolic acid A (20 and 50 μM). Given that low plasma concentrations of Danshen components after oral administration, Danshen preparations may not play pharmacological roles by inhibiting AA ω-hydroxylases; however, as Danshen components may reach high concentration in human intestine, drugs that have an important pre-systemic metabolism by these CYP4A/4F enzymes should avoid being co-administered with Danshen preparations.
Keywords: Arachidonic acid; CYP4A11; CYP4F2; CYP4F3B; Danshen (Salvia miltiorrhiza); Enzyme inhibition; Salvianolic acid; Tanshinone; ω-hydroxylase.
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