Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

Abstract

Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations.

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

“…Sauchinone (over 98% purity) was provided by Professor Chin Y.-W. (Pharmacognosy Laboratory of Dongguk University, Seoul, Korea) according to the modification of previously reported method [ 48 ]. Hydroxybupropion, 4-hydroxymephenytoin, 6-hydroxychlorzoxazone, S -mephenytoin, and pooled human liver microsomes from a mixed pool of 50 donors (HLMs; BD Ultra Pool HLM 50, cat.…”

Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents

“…These herbal constituents might share the same metabolic pathway with the drug, therefore, inhibition of the drug-metabolizing enzyme activity may decrease the drug’s metabolic clearance and increase its level in the body which in turn may lead to toxicity. A recent study reported that sauchinone, an active principle of the herb Saururus chinensis elevated the zidovudine (ZDV) concentration in mice blood by inhibiting UGT2B7 activity [ 15 ]. This can cause haematological toxicity [ 16 ].…”