The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes

Abstract

The aim of this study was to evaluate the in vitro inductive potential of six commonly used trade herbal products on CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Herbal components were extracted from the trade products in a way that ensured a composition equal to that present in the original product. Primary human hepatocytes and specific CYP substrates were used. Classic inducers were used as positive controls and herbal extracts were added in in vivo -relevant concentrations. Metabolites were determined by high performance liquid chromatography (HPLC). St. John's wort and common valerian were the strongest inducing herbs. In addition to induction of CYP3A4 by St. John's wort, common valerian and Ginkgo biloba increased the activity of CYP3A4 and 2D6 and CYP1A2 and 2D6, respectively. A general inhibitory potential was observed for horse chestnut, Echinacea purpurea and common sage. St. John's wort inhibited CYP3A4 metabolism at the highest applied concentration. Horse chestnut might be a herb with high inhibition potentials in vivo and should be explored further at lower concentrations. We show for the first time that G. biloba may exert opposite and biphasic effects on CYP1A2 and CYP2D6 metabolism. Induction of CYP1A2 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations. CYP2D6 activity, regarded generally as noninducible, was increased by exposure to common valerian (linear to dose) and G. bilob a (highest concentration). An allosteric activation is suggested. From the data obtained, G. biloba , common valerian and St. John's wort are suggested as candidates for clinically significant CYP interactions in vivo .The use of herbs as alternative and/or complementary therapy in the Western world is on the rise and gaining increasing popularity. As people often take different herbs in combination with prescribed Western medication [1], there is a potential for both pharmacokinetic and pharmacodynamic herb-drug interactions. In addition to doctor's recommendations [2], patients are also self-medicating with several different herbs and herbal preparations, thinking it is safe [3,4], and often without informing their primary physician.It is important that possible interactions are discovered in order to avoid clinical implications, as shown for example between oral contraceptives and St. John's wort [5], cyclosporine and St. John's wort [6], and between Ginkgo and warfarin [7]. These are just a few of many [8], and we need to identify such harmful combinations in order to avoid serious and negative effects of concurrent use.Cytochrome P450 (CYP) is a superfamily of enzymes, predominantly expressed in the liver, but also in the respiratory tract, lungs, brain and the small intestine [9,10]. CYP isoenzymes are the most important phase 1 enzyme system in the metabolism of xenobiotics, including Western medicines, endogenous compounds and herbal components as effective substrates [11]. Herb-drug interactions can appear when herbs and chemical drugs are co...

Valerian: No evidence for Clinically Relevant interactions

“…The authors conclude that both CYP 3A4 and P-gp interactions are unlikely to be clinically relevant, as the systemic concentrations are probably much lower; therefore, respective IC 50 values for P-gp cannot be reached in vivo. This conclusion is also applicable to their previous study [36] and to their study on CYP 2C19, which showed a weak induction by valerian root extracts [47].…”

“…During the past decade, several potential mechanisms of interactions of valerian preparations, involving CYP enzymes, P-glycoprotein, and UGTs, have been studied in vitro [36,[38][39][40][41][42]46]. Some of these studies pointed to a possible drug interaction potential by valerian extracts.…”

“…[42] used an UGT 1A1 assay to test a commercially available valerian preparation (≥0.1% valerenic acid; extraction medium 70% ethanol, recommended daily dose 1000 mg) for inhibition of human estradiol-3-Oglucuronidation (E-3-G) in the same concentrations as Hellum et al [36]. E-3-G was quantified by HPLC.…”

“…A valerian extract (drug extraction ratio 6 : 1, extraction solvent ethanol 60%) was incubated with human primary hepatocytes for three times within 48 h. The activities of the CYP isoenzymes were determined by analyzing the metabolites of test substances by HPLC [36,46]. The herbal extract concentrations used in in vitro metabolic systems were claimed to cover the whole range of herbal concentrations occurring in vivo.…”

Essentials of Herb-Drug Interactions in the Elderly With Cardiovascular Disease

“…Ginseng may increase cardiac repolarization and QTc interval 160 as well as proarrhythmic risk by additional increase in the bioavailability of antiarrhythmic agents due to reduced metabolism. 161 Siberian ginseng was reported to reproducibly elevate digoxin concentrations, which normalized after discontinuation and increased after resumption of ginseng. 162 Ginsenosides, which include more than 20 saponin glycosides with a nucleus similar in structure to steroid hormones, 163 can cause mastalgia, 164 functionally abnormal vaginal bleeding 165 and gynecomastia in males.…”