Potential Inhibitory and Inducing Effects of Triphala Formulation on Cytochrome P450 Enzymes
DOI:
https://doi.org/10.48048/tis.2022.5819Keywords:
CYP450 inhibition, CYP450 induction, Triphala formulation, Gallic acid, Ellagic acidAbstract
Triphala formulation is one of the most common traditional medicines used for several health conditions. The study aimed to investigate the inhibitory and inducing potentials of Triphala formulation, including its active compounds gallic acid and ellagic acid, on cytochrome P450 (CYP450) enzymes. The inhibitory effects of Triphala formulation, gallic acid and ellagic acid on the 5 major human CYP450 enzymes were evaluated using a bioluminescent CYP450 inhibition assay. Evaluation of inducing effect of Triphala formulation on CYP1A2 and CYP3A1 mRNA expression following daily oral doses of 1,000 and 5,000 mg/kg body weight for 28 days was evaluated using RT-PCR. Gallic acid potently inhibited CYP1A2, CYP2C9 and CYP2C19 with a non-competitive nature, while the inhibitory potencies on CYP2D6 and CYP3A4 were weak. Chronic dosing of Triphala formulation at 1,000 and 3,000 mg/kg body weight significantly induced mRNA expression of CYP1A2 but not CYP3A1. Results suggest the propensity of metabolic drug interactions when Triphala formulation was concurrently administered with other conventional drugs or herbal medicines.
HIGHLIGHTS
- Gallic acid potently inhibited CYP1A2, CYP2C9 and CYP2C19 with a non-competitive nature
- Triphala formulation at the dose of 1,000 and 3,000 mg/kg body weight significantly induced mRNA expression of CYP1A2
- Results suggest the propensity of metabolic drug interactions when Triphala formulation is concurrently administered with conventional drugs or herbal products by human CYP450 enzymes, particularly CYP1A2, CYP2C9 and CYP2C19
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AN Welz, A Emberger-Klein and K Menrad. Why people use herbal medicine: Insights from a focus-group study in Germany. BMC Compl. Alternative Med. 2018; 18, 92.
K Peltzer and S Pengpid. A survey of the training of traditional, complementary, and alternative medicine in universities in Thailand. J. Multidiscip. Healthc. 2019; 12, 119-24.
AM Briggs, JG Persaud, ML Deverell, S Bunzli, B Tampin, Y Sumi, O Amundsen, EMG Houlding, A Cardone, T Hugosdottir, S Rogers, M Pozsgai and H Slater. Integrated prevention and management of non-communicable diseases, including musculoskeletal health: A systematic policy analysis among OECD countries. BMJ Global Health 2019; 4, e001806.
National Institutes of Health National Institute on Aging, U.S. Department of Health and Human Services. Global health and aging, Available at: http://www.who.int/ageing/publications/global_ health.pdf., accessed December 2019.
S Zhou, Y Gao, W Jiang, M Huang, A Xu and JW Paxton. Interactions of herbs with cytochrome P450. Drug Metabol. Rev. 2003; 35, 35-98.
JJ Wu, CZ Ai, Y Liu, YY Zhang, M Jiang, XR Fan, AP Lv and L Yang. Interactions between phytochemicals from traditional Chinese medicines and human cytochrome P450 enzymes. Curr. Drug Metabol. 2012; 13, 599-614.
O Pelkonen, M Turpeinen, J Hakkola, P Honkakoski, J Hukkanen and H Raunio. Inhibition and induction of human cytochrome P450 enzymes: Current status. Arch. Toxicol. 2008; 82, 667-715.
J Papadopoulos and PL Smithburger. Common drug interactions leading to adverse drug events in the intensive care unit: Management and pharmacokinetic considerations. Crit. Care Med. 2010; 38, S126-S135.
S Shi and U Klotz. Drug interactions with herbal medicines. Clin. Pharmacokinet. 2012; 51, 77-104.
JH Lin and AY Lu. Inhibition and induction of cytochrome P450 and the clinical implications. Clin. Pharmacokinet. 1998; 35, 361-90.
YWF Lam, SM Huang and SD Hall. Herbal supplements - drug interactions: Scientific and regulatory perspectives. Taylor & Francis Group, New York, 2006.
R Delgoda and ACG Westlak. Herbal interactions involving cytochrome p450 enzymes: A mini review. Toxicol. Rev. 2004; 23, 239-49.
Z Hu, X Yang, PCL Ho, SY Chan, PWS Heng, E Chan, W Duan, HL Koh and S Zhou. Herb-drug interactions. Drugs 2005; 65, 1239-82.
T Wongsri, E Srisook, P. Rongnoparut and S Sarapusit. Inhibitory activity of some medicinal folk plants from Chantaburi Province on the cytochrome P450 3A4 enzyme. In: Proceedings of the 8th Thailand-Japan International Academic Conference, Tokyo, Japan. 2016.
BH Hellum, Z Hu and OG Nilsen. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic Clin. Pharmacol. 2007; 100, 23-30.
AA Izzo. Interactions between herbs and conventional drugs: Overview of the clinical data. Med. Princ. Pract. 2012; 21, 404-28.
SC Piscitelli, AH Burstein, N Welden, KD Gallicano and J Falloon. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin. Infect. Dis. 2002; 34, 234-8.
PK Mukherjee, S Rai, S Bhattacharya, A Wahile and BP Saha. Marker analysis of polyherbal formulation, Triphala - a well known Indian traditional. Indian J. Tradit. Knowl. 2008; 7, 379-83.
MC Sabu and R Kuttan. Anti-diabetic activity of medicinal plants and its relationship with their antioxidant property. J. Ethnopharmacol. 2002; 81, 155-60.
PK Mukherjee, S Rai, S Bhattacharya, PK Debnath, TK Biswas, U Jana, S Pandit, BP Saha and PK Paul. Clinical study of ‘Triphala’ - a well known phytomedicine from India. Iranian J. Pharmacol. Therapeut. 2006; 5, 51-4.
A Wongnoppavich, J Kanjana and S Seewaboon. Triphala: The Thai traditional herbal formulation for cancer treatment. Songklanakarin J. Sci. Tech. 2009; 31, 139-49.
Y Takauji, K Miki, J Mita, MN Hossain, M Yamauchi, M Kioi, D Ayusawa and M Fujii. Triphala, a formulation of traditional Ayurvedic medicine, shows protective effect against X-radiation in HeLa cells. J. Biosci. 2016; 41, 569-75.
MS Baliga, S Meera, B Mathai, MP Rai, V Pawar and PL Palatty. Scientific validation of the ethnomedicinal properties of the Ayurvedic drug Triphala: A review. Chin. J. Integr. Med. 2012; 18, 946-54.
CT Peterson, K Denniston and D Chopra. Therapeutic uses of Triphala in Ayurvedic medicine. J. Alternative Compl. Med. 2017; 23, 607-14.
MS Baliga. Triphala, Ayurvedic formulation for treating and preventing cancer: A review. J. Alternative Compl. Med. 2010; 16, 1301-8.
P Phetkate, T Plengsuriyakarn, K Bangchang, P Rinthong, S Kietinun and K Sriyakul. Acute and subacute oral toxicity evaluation of the water extract of Triphala formulation in rats. Int. J. Biol. Pharm. Allied Sci. 2019; 8, 779-92.
GH Naik, KI Priyadarsini and H Mohan. Free radical scavenging reactions and phytochemical analysis of triphala, an ayurvedic formulation. Curr. Sci. 2006; 90, 1100-5.
P Phetkate, T Kummalue, P Rinthong, S Kietinun and K Sriyakul. Study of the safety of oral Triphala aqueous extract on healthy volunteers. J. Integr. Med. 2020; 18, 35-40.
RK Lall, DN Syed, VM Adhami, MI Khan and H Mukhtar. Dietary polyphenols in prevention and treatment of prostate cancer. Int. J. Mol. Sci. 2015; 16, 3350-76.
MT Mansouri, M Soltani, B Naghizadeh, Y Farbood, A Mashak and A Sarkaki. A possible mechanism for the anxiolytic-like effect of gallic acid in the rat elevated plus maze. Pharmacol. Biochem. Behav. 2014; 117, 40-6.
YS Kim, T Zerin and HY Song. Antioxidant action of ellagic acid ameliorates paraquat-induced A549 cytotoxicity. Biol. Pharm. Bull. 2013; 36, 609-15.
S Ponnusankar, S Pandit, R Babu, A Bandyopadhyay and PK Mukherjee. Cytochrome P450 inhibitory potential of Triphala - a Rasayana from Ayurveda. J. Ethnopharmacol. 2011; 133, 120-5.
TM Vijayakumar, RM Kumar, A Agrawal, GP Dubey and K Ilango. Comparative inhibitory potential of selected dietary bioactive polyphenols, phytosterols on CYP3A4 and CYP2D6 with fluorometric high-throughput screening. J. Food Sci. Tech. 2015; 52, 4537-43.
P Phetkate, T Kummalue, Y U-pratya and S Kietinun. Significant increase in cytotoxic T lymphocytes and natural killer cells by triphala: A clinical phase I study. Evid. Base. Compl. Alternatative Med. 2012; 2012, 239856.
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals, Available at: https:// www.ncbi.nlm.nih.gov/books/NBK54050/, accessed January 2018.
H Jung and S Lee. Inhibition of human cytochrome P450 enzymes by allergen removed rhus verniciflua stoke standardized extract and constituents. Evid. Base. Compl. Alternatative Med. 2014; 2014, 150351.
S Ramasamy, LV Kiew and LY Chung. Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents. Molecules 2014; 19, 2588-601.
JM Berg, JL Tymoczko and L Stryer. Enzymes: Basic concepts and kinetics, appendix: Vmax and KM can be determined by double-reciprocal plots. Biochemistry. 5th edition. New York: W H Freeman, 2002.
JJ Cali, A Niles, MP Valley, MA O'Brien, TL Riss and J Shultz. Bioluminescent assays for ADMET. Expet. Opin. Drug Metabol. Toxicol. 2008; 4, 103-20.
JJ Cali, D Ma, M Sobol, DJ Simpson, S Frackman, TD Good, WJ Daily and D Liu. Luminogenic cytochrome P450 assays. Expet. Opin. Drug Metabol. Toxicol. 2006; 2, 629-45.
VV Roshchina, AV Kuchin and VA Yashin. Application of autofluorescence for analysis of medicinal plant. Int. J. Spectros. 2017; 2017, 7159609.
VV Roshchina, AV Kuchin and VA Yashin. Autofluorescence of plant secretory cells as possible tool for pharmacy. Int. J. Pharm. Chem. 2016; 2, 31-8.
M Ashour, F Youssef, H Gad and M Wink. Inhibition of cytochrome P450 (CYP3A4) activity by extracts from 57 plants used in Traditional Chinese Medicine (TCM). Pharmacogn. Mag. 2017; 13, 300-8.
K Kaneko, K Suzuki, E Iwadate-Iwata, I Kato, K Uchida and M Onoue. Evaluation of food-drug interaction of guava leaf tea. Phytother. Res. 2013; 27, 299-305.
M Alnaqeeb, KA Mansor, EM Mallah, BY Ghanim, N Idkaidek and NA Qinna. Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts. BMC Compl. Med. Ther. 2019; 19, 29.
DA Sychev, GM Ashraf, AA Svistunov, ML Maksimov, VV Tarasov, VN Chubarev, VA Otdelenov, NP Denisenko, GE Barreto and G Aliev. The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo. Drug Des. Dev. Ther. 2018; 12, 1147-56.
K Klein and UM Zanger. Pharmacogenomics of cytochrome P450 3A4: Recent progress toward the “Missing Heritability” problem. Front. Genet. 2013; 4, 12.
M Ingelman-Sundberg. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005; 5, 6-13.
SF Zhou. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin. Pharmacokinet. 2009; 48, 689-723.
J Kirchheiner, C Heesch, S Bauer, C Meisel, A Seringer, M Goldammer, M Tzvetkov, I Meineke, I Roots and J Brockmöller. Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther. 2004; 76, 302-12.
BL Athukuri and P Neerati. Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: Involvement of CYP2D6 inhibition. Drug Metabol. Personized Ther. 2016; 31, 229-34.
BL Athukuri and P Neerati. Enhanced oral bioavailability of diltiazem by the influence of gallic acid and ellagic acid in male wistar rats: Involvement of CYP3A and P-gp inhibition. Phytother. Res. 2017; 31, 1441-8.
CR Lee, JA Goldstein and JA Pieper. Cytochrome P450 2C9 polymorphisms: A comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12, 251-63.
SJ Lee. Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine. Front. Genet. 2012; 3, 318.
L Stupans, HW Tan, A Kirlich, K Tuck, P Hayball and M Murray. Inhibition of CYP3A-mediated oxidation in human hepatic microsomes by the dietary derived complex phenol, gallic acid. J. Pharm. Pharmacol. 2002; 54, 269-75.
C Manach, G Williamson, C Morand, A Scalbert and C Remesy. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 2005; 81, 230S-242S.
S Shahrzad, K Aoyagi, A Winter, A Koyama and I Bitsch. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J. Nutr. 2001; 131, 1207-10.
ZY Wang, M Das, DR Bickers and H Mukhtar. Interaction of epicatechins derived from green tea with rat hepatic cytochrome P-450. Drug Metabol. Dispos. 1988; 16, 98-103.
OS Sohn, A Surace, ES Fiala, JP Richie, S Colosimo, E Zang and JH Weisburger. Effects of green and black tea on hepatic xenobiotic metabolizing systems in the male F344 rat. Xenobiotica 1994; 24, 119-27.
Y Konishi, Y Hitomi and E Yoshioka. Intestinal absorption of p-coumaric and gallic acids in rats after oral administration. J. Agr. Food Chem. 2004; 52, 2527-32.
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