In vitro inhibitory effects of components from Salvia miltiorrhiza on catalytic activity of three human Arachidonic acid omega-hydroxylases

CYP4 enzymes are involved in the metabolism of xenobiotics and endogenous molecules. 20Hydroxyeicosatetraenoic acid (20-HETE), the arachidonic acid (AA) omega-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 omega-hydroxylation using recombinant CYP4A11, CYP4F2, CYP4F3B, and microsomal systems. Tanshinone IIA had noncompetitive inhibition on CYP4F3B (K-i = 4.98 mu M). Cryptotanshinone (K-i = 6.87 mu M) and tanshinone I (K-i = 0.42 mu M) had mixed-type inhibition on CYP4A11. Dihydrotanshinone I had mixed-type inhibition on CYP4A11 (K-i = 0.09 mu M), and noncompetitive inhibition on CYP4F2 (K-i = 4.25 mu M) and CYP4F3B (K-i = 3.08 mu M). Salvianolic acid A had competitive inhibition on CYP4A11 (K-i = 19.37 mu M), and noncompetitive inhibition on CYP4F2 (K-i = 15.28 mu M) and CYP4F3B (K-i = 6.45 mu M). Salvianolic acid C had noncompetitive inhibition on CYP4F2 (K-i = 5.70 mu M) and CYP4F3B (K-i = 18.64 mu M). In human kidney, human liver or rat heart microsomes, 20-HETE formation was significantly inhibited (P < 0.05) by dihydrotanshinone I (5 and 20 mu M) and salvianolic acid A (20 and 50 mu M). Given that low plasma concentrations of Danshen components after oral administration, Danshen preparations may not play pharmacological roles by inhibiting AA omega-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. (C) 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.