Abstract
Opuntia ficus indica (OFI) is grown abundantly in arid areas and its fruits are regarded as an important food and nutrient source owing to the presence of flavonoids, minerals, and proteins. The previous report that OFI exerts phytoestrogenic activity makes it plausible for OFI-containing supplements to be used as alternative estrogen replacement therapy. In the case of polypharmacy with the consumption of OFI-containing botanicals in post- or peri-menopausal women, it is critical to determine the potential drug-OFI interaction due to the modulation of drug metabolism. In the present study, the modulating effects on the hepatic drug metabolizing enzymes (DMEs) by OFI and its flavonoid constituents (kaempferol, quercetin, isorhamnetin, and their glycosidic forms) were investigated using the liver microsomal fractions prepared from ovariectomized (OVX) rats, human liver microsomes, and human hepatocarcinoma cell line (HepG2). As a result, the oral administration of extracts of OFI (OFIE) in OVX rats induced hepatic CYP2B1, CYP3A1, and UGT2B1. OFIE, hydrolyzed (hdl) OFIE, and several flavonols induced the transcriptional activities of both CYP2B6 and CYP3A4 genes in HepG2 cells. Finally, OFIE did not inhibit activities of cytochrome P450 (CYPs) or uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), whereas hdl OFIE or flavonol treatment inhibited CYP1A2 and CYP3A1/3A4 in rat and human liver microsomes. Our data demonstrate that OFIE may induce or inhibit certain types of DMEs and indicate that drug-OFI interaction may occur when the substrate or inhibitor drugs of specific CYPs or UGTs are taken concomitantly with OFI-containing products.
Highlights
Drug-herb interactions (DHIs) refer to phenomena where the pharmacokinetic or pharmacological behavior of a certain drug is modulated by herb constituents that are orally coadministered with the drug
The concentrations of flavonoids employed in the reported studies were in the μM range, which are approximately hundreds of fold higher compared to those of OFIE used in the present study
CAR binds to the phenobarbital responsive element module (PBREM), whereas PXR interacts with the xenobiotic response element (XRE) to activate the transcription of downstream target genes such as CYP2B6 and CYP3A4, respectively [22]
Summary
Drug-herb interactions (DHIs) refer to phenomena where the pharmacokinetic or pharmacological behavior of a certain drug is modulated by herb constituents that are orally coadministered with the drug. DHI is regarded as one of the critical clinical concerns in the population who have a tendency of concomitant consumption of herb and prescribed drugs [1]. One of the major mechanisms of DHIs is the induction or inhibition of drug metabolizing enzymes (DMEs) [1,2]. Age-related changes in the liver can affect the capacity for drug metabolism and sex hormones are reported to influence the expression and activities of CYPs and UGTs [4,5,6]. DHI is an important clinical concern when herbal supplements and prescribed medicines are consumed concomitantly in the elderly, whose drug metabolism capacity is affected by factors such as aging and low level of sex hormones [7]. Intensive studies in preclinical or clinical settings to investigate the effects of age, sex, or polypharmacy on DHI outcomes are scarce due to a lack of focus on DHIs and inherent difficulties in study execution in the elderly population
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