Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C

Abstract

Magnolol (MAG; 5,5'-diallyl-2,2'-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC50 of 1.62 μM) and 2C (IC50 of 5.56 μM), while weakly CYP3A (IC50 of 35.0 μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (Ki of 1.09-12.0 μM); competitive inhibitor for CYP2C (Ki of 10.0-15.2 μM) and 3A (Ki of 93.7-183 μM). Based on the comparison of the current IC50 and Ki values with a previously reported liver concentration (about 13 μM) of MAG after its seven times oral administration at a dose of 50 mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG-drug interactions.

Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

“…Several medicinal herbs, including Allium sativum, Camellia sinensis, Ginkgo biloba, Glycyrrhiza glabra, Coptidis rhizoma, Silybi fructus, and St. John's wort are associated with herb-drug interactions attributable to inhibition and/or induction of drug-metabolizing enzymes [14][15][16][17]. Several lignans including honokiol [18], machilin A [19], magnolol [20], schizandrins [21], schizandrol B [22], phyllantin, hypophyllantin [23], and podophyllotoxin [24] cause herb-drug interactions featuring inhibition of CYP enzymes.…”

Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

“…Does Magnolol bind to microtubule directly or through binding to other indirect molecules? In addition, although there was a report to test some symbolic parameters of pharmacokinetics and pharmacodynamics (PDPK) on Magnolol in vivo [44], there is still an urgent need to determine more specific PDPK characteristics before its clinical utilization in NSCLC treatment.…”

In vitro metabolism of magnolol and honokiol in rat liver microsomes and their interactions with seven cytochrome P substrates

“…It generated m / z 277.0871, 251.1078, 233.0972, 231.0812, 209.0608, and other fragment ions in MS 2 , which respectively represent loss of one molecule of water; a molecule of water, a carbonyl group, and hydrogenation; two hydroxyl groups and one carbonyl group; two molecules of water and one carbonyl group; and one propenyl group, one carbonyl group, and one molecule of water. It is speculated that these products are derived from the oxidative hydrolysis and dehydrogenation of the terminal olefin . The secondary mass spectrum is shown in Figure a.…”