Polysaccharide peptides from Coriolus versicolor competitively inhibit model cytochrome P450 enzyme probe substrates metabolism in human liver microsomes

Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy or health supplement in China. Previous studies have shown that PSP decreased antipyrine clearance and inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation and in human CYP2C9. In this study, the effects of the water extractable fraction of PSP on the metabolism of model CYP1A2, CYP2D6, CYP2E1 and CYP3A4 probe substrates were investigated in pooled human liver microsomes. PSP (1.25–20 μM) dose-dependently decreased CYP1A2-mediated metabolism of phenacetin to paracetamol (IC50 19.7 μM) and CYP3A4-mediated metabolism of testosterone to 6β-hydroxytestosterone (IC20 7.06 μM). Enzyme kinetics studies showed the inhibition of CYP1A2 activity was competitive and concentration-dependent (Ki = 18.4 μM). Inhibition of testosterone to 6β-hydroxytestosterone was also competitive and concentration-dependent (Ki = 31.8 μM). Metabolism of dextromethorphan to dextrorphan (CYP2D6-mediated) and chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1-mediated) was only minimally inhibited by PSP, with IC20 values at 15.6 μM and 11.9 μM, respectively. This study demonstrated that PSP competitively inhibited the CYP1A2- and CYP3A4-mediated metabolism of model probe substrates in human liver microsomes in vitro. The relatively high Ki values for CYP1A2 and CYP3A4 would suggest a low potential for PSP to cause herb–drug interaction related to these CYP isoforms.