A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

Abstract

Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2–33.7 μM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.

Acetylshikonin is a novel non‐selective cytochrome P450 inhibitor

“…(IC 50 > 50 μM) (Table 1). In a previous study, SKF-525A was also reported to weakly inhibit CYP1A2, CYP2A6, and CYP2E1 with an IC 50 in the range 50-1100 μM (Emoto et al, 2005;Song et al, 2014).…”

“…SKF‐525A, which is the most commonly used general P450 inhibitor in reaction phenotyping studies, showed strong inhibitory effects against CYP2B6, CYP2C19 and CYP2D6, with IC 50 values of 2.5, 3.6 and 0.5 μ m , respectively, whereas it had no inhibitory effects against CYP1A2, CYP2A6, CYP2E1 or CYP2J2 (IC 50 > 50 μ m ) (Table ). In a previous study, SKF‐525A was also reported to weakly inhibit CYP1A2, CYP2A6, and CYP2E1 with an IC 50 in the range 50–1100 μ m (Emoto et al, ; Song et al, ) . Similar to the previous results (Song et al, ), thelephoric acid, which is isolated from Polyozellus multiplex , moderately inhibited CYP2C8‐mediated amodiaquine O ‐deethylation and CYP2C9‐mediated tolbutamide hydroxylation, with IC 50 values of 6.9 and 11.4 μ m , respectively.…”

“…In a previous study, SKF‐525A was also reported to weakly inhibit CYP1A2, CYP2A6, and CYP2E1 with an IC 50 in the range 50–1100 μ m (Emoto et al, ; Song et al, ) . Similar to the previous results (Song et al, ), thelephoric acid, which is isolated from Polyozellus multiplex , moderately inhibited CYP2C8‐mediated amodiaquine O ‐deethylation and CYP2C9‐mediated tolbutamide hydroxylation, with IC 50 values of 6.9 and 11.4 μ m , respectively. Thelephoric acid showed strong inhibitory activities against CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP2E1 and CYP3A (IC 50 < 5 μ m ) (Table ).…”

“…This study evaluated the inhibitory potential of acetylshikonin against ten P450 isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2 and 3A) and compared them with those of SKF‐525A (Franklin & Hathaway, ) and thelephoric acid (Song et al, ), known non‐specific P450 inhibitors. SKF‐525A, which is the most commonly used general P450 inhibitor in reaction phenotyping studies, showed strong inhibitory effects against CYP2B6, CYP2C19 and CYP2D6, with IC 50 values of 2.5, 3.6 and 0.5 μ m , respectively, whereas it had no inhibitory effects against CYP1A2, CYP2A6, CYP2E1 or CYP2J2 (IC 50 > 50 μ m ) (Table ).…”

“…SKF-525A (2-diethylaminoethyl-2,2-diphenylvalerate-HCl) is one of the most widely used non-selective P450 inhibitors, and has been used to determine whether a drug is metabolized by P450 enzymes (Emoto, Murase, Sawada, Jones, & Iwasaki, 2003;Franklin & Hathaway, 2008). SKF-525A has inhibitory effects against CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, but not against CYP1A2, CYP2A6 or CYP2E1 (the IC 50 values for these three are > 50 μM) (Emoto et al, 2003;Emoto, Murase, Sawada, & Iwasaki, 2005;Song et al, 2014). Another useful non-specific P450 inhibitor is 1-aminobenzotriazole (ABT), which is thought to inactivate P450 enzymes following complex formation with metabolic intermediates (MI) (Linder et al, 2009).…”