Elsevier

Food and Chemical Toxicology

Volume 100, February 2017, Pages 80-89
Food and Chemical Toxicology

Effects of peppermint tea consumption on the activities of CYP1A2, CYP2A6, Xanthine Oxidase, N-acetyltranferase-2 and UDP-glucuronosyltransferases-1A1/1A6 in healthy volunteers

https://doi.org/10.1016/j.fct.2016.12.021Get rights and content

Highlights

  • Peppermint tea consumption reduces NAT2 activity in humans.

  • Peppermint tea consumption possibly reduces CYP1A2 activity in humans.

  • Peppermint tea does not affect CYP2A6, Xanthine Oxidase and UDP-glucuronosyltransferases 1A1/1A6 activity in humans.

Abstract

Peppermint leaves are widely used for the symptomatic treatment of digestive disorders. Previous studies have shown significant effects of its natural products on human enzyme activity; however, there is no study available concerning the effects of peppermint tea on metabolizing enzymes in humans. Aim of the present study was to investigate the effect of peppermint tea on CYP1A2, CYP2A6, Xanthine Oxidase (XO), N-acetyltranferase-2 (NAT2) and UDP-glucuronosyltransferases-1A1/1A6 (UGT1A1/1A6) activities in healthy subjects. Four males and five females consumed peppermint tea (2 g of dry leaves/200 mL water, twice daily) for six days. CYP1A2, CYP2A6, XO, NAT2 and UGT1A1/1A6 activities were determined before and at the end of the study period, using the following caffeine and paracetamol metabolic ratios: CYP1A2: 17MX/137MX (saliva) and (AFMU+1MU+1MX)/17MU (urine); CYP2A6: 17MU/(17MU + 17MX), XO: 1MU/(1MU+1MX), NAT2, AFMU/(AFMU+1MU+1MX) and UGT1A1/1A6 glucuronidated/total paracetamol, all determined in urine. NAT2 metabolic ratio was significantly reduced following peppermint consumption (0.15 ± 0.13 vs 0.14 ± 0.13; p < 0.05). CYP1A2 urine and saliva indices were reduced, yet not significantly, following peppermint consumption (urine: 3.17 ± 1.08 vs 2.91 ± 0.76, saliva: 0.56 ± 0.12 vs 0.50 ± 0.12; p > 0.05). Peppermint had no influence on CYP2A6, XO and UGT1A1/1A6 indices. Daily ingestion of peppermint tea may alter pharmacokinetics of clinically administered drugs and promote cancer chemoprevention through NAT2 inhibition.

Introduction

Herbal medicines hold a strong tradition in treating diseases outside conventional medicine inasmuch as plants and their derivatives have been used as remedies since antiquity. Advance in clinical research has drawn significant attention to global health debates as for the value of herbal medicine in disease management. It is of interest that eighty per cent of African populations use some form of traditional herbal medicine and the worldwide annual market for these products approaches 60 billion US$ (Tilburt and Kaptchuk, 2008). Furthermore, it is anticipated that traditional herbal medicine research will play a critical role in global health in the future (Tilburt and Kaptchuk, 2008).

In this endeavor we report the health beneficial effects exhibited by the peppermint decoction, a popular beverage widely known for its refreshing taste and peculiar aroma, produced from Mentha piperita L., a Mediterranean basin originated plant. The latter is traditionally used as source of valuable natural products (Lawrence, 2006). In addition, it is used in soothing several digestive disorders, such as dyspepsia, flatulence, gastritis, enteritis and is also used as a cholagogue (European Medicines Agency, 2008). Currently, peppermint oil is used for the safe and effective short-term treatment of active irritable bowel syndrome (Alam et al., 2013, Khanna et al., 2014). Besides its significant benefits to the digestive tract, peppermint has also been identified to display significant in vitro antioxidant, antitumor, antiallergenic, antiviral, fungicidal and antibacterial activity (Lv et al., 2012, McKay and Blumberg, 2006). Moreover, animal model studies have indicated that peppermint prevents or reduces carcinogenesis, exhibits antiallergenic and anti-inflammatory activities and exerts analgesic and local anesthetic actions (McKay and Blumberg, 2006).

CYP1A2, a member of the cytochrome P450 superfamily (CYPs) is involved in the metabolism of over 25 drugs and the metabolic activation of several procarcinogens, including aromatic and heterocyclic amines, nitroaromatic compounds, and mycotoxins (Landi et al., 1999, Faber et al., 2005). Wide interindividual differences in CYP1A2 activity have been described that could be attributed to factors such as gender, race, genetic polymorphisms, and exposure to inducers or inhibitors (Landi et al., 1999, Pelkonen et al., 2008). Individual differences in CYP1A2 activity may influence the therapeutic efficacy of some drugs and even the susceptibility to cancer risk (Landi et al., 1999).

CYP2A6 is also a member of the cytochrome P450 superfamily involved in the metabolism of many drugs and in the bioactivation of several procarcinogens such as nitrosamines and aflatoxins (Di et al., 2009). Its activity displays wide interindividual variation primarily due to genetic polymorphisms and it is modified by certain drugs, diseases and environmental factors (Di et al., 2009).

Xanthine oxidase (XO) is one of the two interconvertible forms of the enzyme Xanthine oxidoreductase (XOR) which is present in the cytoplasm and on the outer surface of the cell membrane (Harrison, 2002). Its physiological role has been associated with purine catabolism and oxidation of endogenous substrates. Furthermore, it can also metabolize different xenobiotics, such as antiviral and anticancer agents, thus, contributing to detoxification (Pritsos, 2000, Battelli et al., 2014).

N-acetyltransferase-2 (NAT2) is a cytosolic enzyme with highest activity in the liver and intestine. It is a phase II enzyme responsible for the acetylation of about 25 prescribed drugs. In addition, NAT2 participates in the metabolism of environmental carcinogens including aromatic and heterocyclic amines (Dupret and Rodrigues-Lima, 2005). It is a polymorphic enzyme with 107 alleles which arise from the combination of 43 point mutations (Arylamine N-acetyltransferases database).

UDP-glucuronosyltransferases (UGTs) comprise a major family of hepatic microsomal enzymes responsible for catalyzing the conjugation of d-glucuronic acid with a wide range of xeno- and endobiotics. UGTs are key enzymes in the metabolism of many drugs, carcinogens and other xenobiotics (Burchell et al., 2005). The subfamilies primarily responsible for the metabolism of xenobiotics are UGT1A and 2B (Fisher et al., 2000). It has been shown that UGT1A1, among other isoforms, has the highest capacity to detoxify foodborne carcinogenic heterocyclic amine PhIP (Malfatti and Felton, 2001), while, UGT1A6 is more active toward detoxification of the polycyclic aromatic hydrocarbon (PAH) benzo(α)pyrene (Mackenzie et al., 1993).

The in vivo activity of the above-mentioned enzymes can be determined by using of specific probe drugs which act as substrates for these enzymes. Caffeine is an innocuous substrate for several drug metabolizing enzymes and has been widely used as a probe for the in vivo determination of CYP1A2, CYP2A6, XO and NAT2 activities (Hakooz, 2009). Similarly, paracetamol has been used as a probe for the determination of the in vivo activity of UGTA1A1 and 1A6 as 50–70% of paracetamol elimination is carried out through glucuronidation catalyzed by these UGT isoforms (Bock et al., 1994, McGill and Jaeschke, 2013).

The modulation of xenobiotic metabolizing enzymes by herbal natural products as a chemoprevention mechanism toward carcinogenicity has gained great interest (Wanwimolruk and Prachayasittikul, 2014). Moreover, potential substrate interactions between natural products and clinically administered drugs may lead to significant clinical implications (Wanwimolruk and Prachayasittikul, 2014). The influence of different natural products on the in vivo activity of human cytochrome P450 (reviewed by Wanwimolruk and Prachayasittikul, 2014, Wanwimolruk et al., 2014) and XO, NAT2, UGTs or Sulfotranferases (SULTs) (Wenk et al., 2004, Chen et al., 2011, Volak et al., 2013) has been reported in conflicting studies showing either inhibition or induction of the natural products on enzyme activity. However, no study is available to date on the effect of peppermint tea on metabolic enzymes in humans. In fact, data of the effect of peppermint tea on enzyme activity is limited to an experimental animal study showing significant modulation of phase I and phase II drug metabolizing enzymes (Maliakal and Wanwimolruk, 2001). Therefore, the purpose of the present study was to explore the effect of peppermint tea on the in vivo activity of the xenobiotic metabolizing enzymes CYP1A2, CYP2A6, XO, NAT2 and UGT1A1/1A6 in healthy volunteers using caffeine and paracetamol as probe-drugs.

Section snippets

Materials

Hesperidin was purchased from Acros Organics, diosmin, rosmarinic acid, myricetin, diosmetin from Extrasynthese, (+)-catechin, eriodictyol, luteolin, apigenin, naringenin, chlorogenic acid, rutin, eriocitrin, hesperetin, narirutin, salvianolic acid and lithospermic acid were purchased from Sigma-Aldrich. Water, acetonitrile, and acetic acid were purchased from Merck (Darmstadt, Germany), all as LC-MS grades. PTFE filters (0.45 μm) were obtained from Macherey-Nagel, Germany.

Caffeine metabolites

Bioactive chemicals composition of peppermint tea

The plant material dissolved in hot water in each batch (2 g) of peppermint tea was 584.3 mg, corresponding to a 29.2% yield. The qualitative and quantitative assessment of the chemical composition of the peppermint tea in terms of bioactive compounds was performed using HPLC-UV complemented with HPLC-ESI/MS for the quantitative analysis of non UV sensistive compounds, such as hesperetin. The respective results are presented in Table 1.

These analytical results are in line with those reported in

Discussion

To the best of our knowledge this is the first study to examine the effect of peppermint tea consumption on the in vivo activity of the human xenobiotic phase I metabolizing enzymes CYP1A2, CYP2A6, XO and phase II enzymes NAT2 and UGT1A1/1A6. Caffeine was used as a metabolic probe for CYP1A2, CYP2A6, XO and NAT2, whereas paracetamol was used as a probe to assess UGT1A1 and UGT1A6 combined activities. NAT2-related ratios were significantly lower in volunteers after six days of peppermint tea

Conclusions

Six days of peppermint tea consumption reduces NAT2 activity significantly in healthy humans. Our preliminary results indicate that CYP1A2 activity is also reduced, yet not significantly. Conversely, the in vivo activities of the xenobiotic metabolizing enzymes CYP2A6, XO and UGT1A1/1A6 is not altered following peppermint tea consumption. The significant effect of peppermint tea on NAT2 activity may influence the elimination of several clinically used drugs which are substrates of NAT2 and may

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