Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis

Abstract

Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π-π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%-321% and 2%-3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.

Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

“…Deoxyshisandrin, a CYP3A inhibitor, markedly increases plasma concentrations of midazolam in rats [ 52 ]. The magnitude of AUC variation for drugs that are predominantly biotransformed by CYP3A4 was estimated to increase by 22–321% in the presence of gomisin C, a strong CYP3A inhibitor [ 17 ].…”

“…Moreover, schisandrin and gomisin A were found to inhibit recombinant CYP3A4 activity with A few in vitro studies investigating the modulatory effects of individual dibenzocyclooctadiene lignans on P450 enzyme activities have been carried out. For example, previous studies found that gomisin A, -C, and -G inhibit CYP3A-mediated midazolam 1 -hydroxylation with IC 50 values of 1.86 µM, 0.059 µM, and 0.19 µM in a recombinant CYP3A4 isoform, respectively [17,18], while schisandrin A inhibits CYP2C19-catalyzed omeprazole hydroxylation with an IC 50 of 86.4 µM in recombinant CYP2C19 [19]. Moreover, schisandrin and gomisin A were found to inhibit recombinant CYP3A4 activity with IC 50 values of 32.0 and 1.39 µM, respectively [20].…”

Schisandrol A and gomisin N from Schisandra chinensis extract improve hypogonadism via anti-oxidative stress in TM3 Leydig cells

“…The modulating effects of lignans have recently been linked to cytochrome P450 enzymatic activities. For example, gomisin compounds (A, C, and G) and schisandrin A suppress CYP3A and CYP2C19, respectively [ 19 ]. In addition, gomisin A and schisandrin A inhibit CYP3A4 activity [ 20 ].…”

Schisandra chinensis, Five Flavor Berry, a Traditional Chinese Medicine and a Super-Fruit from North Eastern China

“…Schisandra chinensis has been used because of multiple pharmacological activities alone or in the combination with other drugs for many years. 14,15 It is one of the oldest medicinal plants used in East of Asia, especially traditional Chinese medicine. [16][17][18] Chinese magnolia vine (Schisandra chinensis) is used in both traditional and modern Chinese medicine.…”