Download PDF
Drug Res (Stuttg) 2015; 65(07): 366-372
DOI: 10.1055/s-0034-1384604
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver

H. M. Korashy
1   Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
F. I. Al-Jenoobi
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
M. Raish
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
A. Ahad
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
A. M. Al-Mohizea
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
M. A. Alam
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
K. M. Alkharfy
3   Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
4   Biomarkers Research Program, King Saud University, Riyadh, Saudi Arabia
,
S. A. Al-Suwayeh
2   Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
› Author Affiliations
Further Information

Publication History

received 09 May 2014

accepted 02 July 2014

Publication Date:
06 August 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Aim: Combined use of herbs and drugs may result in clinically important herb-drug interactions. The majorities of these interactions are thought to be metabolism-based and involve induction or inhibition of cytochrome P450 (CYP). The current study was designed to investigate the effect of some commonly used herbs on rat CYP2C11 gene expression and metabolic activity.

Methods: Wistar rats were treated for 7 days with increasing doses of 3 herbs; Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida. Thereafter, CYP2C11 mRNA and protein levels were determined by real-time polymerase chain reaction (RT-PCR) and western blot analyses, respectively. In vitro metabolic activity of CYP2C11 was performed on rat hepatic microsomes using tolbutamide as specific substrate.

Results: Our results showed that all the 3 herbs significantly inhibited the mRNA and protein expression levels of CYP2C11 in a dose-dependent manner. Furthermore, the in vitro enzyme metabolic activity study showed a significant decrease in the formation of 4-hyroxy-tolbutamide, a tolbutamide metabolite, at the higher doses. The inhibitory effects of the investigated herbs on rat CYP2C11 was in the order: Nigella Sativa > Trigonella foenum-graecum > Ferula asafoetida.

Conclusions: The 3 herbs are strong inhibitor of CYP2C11 expression, which can lead to an undesirable pharmacological effect of clinically used CYP2C11 substrate drugs with a low therapeutic index.

Key words

CYP2C - gene expression - herb-drug interaction - rat microsomes
 

  • References

  • 1 Bayrak O, Bavbek N, Karatas OF et al. Nigella sativa protects against ischaemia/reperfusion injury in rat kidneys. Nephrol Dial Transplant 2008; 23: 2206-2212
    CrossrefPubMedGoogle Scholar
  • 2 Ibrahim ZS, Ishizuka M, Soliman M et al. Protection by Nigella sativa against carbon tetrachloride-induced downregulation of hepatic cytochrome P450 isozymes in rats. Jpn J Vet Res 2008; 56: 119-128
    PubMedGoogle Scholar
  • 3 Gurley BJ, Gardner SF, Hubbard MA et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002; 72: 276-287
    CrossrefPubMedGoogle Scholar
  • 4 Huang SM, Lesko LJ. Drug-drug drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned?. J Clin Pharmacol 2004; 44: 559-569
    CrossrefPubMedGoogle Scholar
  • 5 Rettie AE, Jones JP. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol 2005; 45: 477-494
    CrossrefPubMedGoogle Scholar
  • 6 Yeung JH, Chan SL, Or PM. Polysaccharide peptides from COV-1 strain of Coriolus versicolor inhibit tolbutamide 4-hydroxylation in the rat in vitro and in vivo. Food Chem Toxicol 2006; 44: 1414-1423
    CrossrefPubMedGoogle Scholar
  • 7 Brazier NC, Levine MA. Drug-herb interaction among commonly used conventional medicines: a compendium for health care professionals. Am J Ther 2003; 10: 163-169
    CrossrefPubMedGoogle Scholar
  • 8 Markowitz JS, DeVane CL. The emerging recognition of herb-drug interactions with a focus on St. John’s wort (Hypericum perforatum). Psychopharmacol Bull 2001; 35: 53-64
    PubMedGoogle Scholar
  • 9 Williamson EM. Drug interactions between herbal and prescription medicines. Drug Saf 2003; 26: 1075-1092
    CrossrefPubMedGoogle Scholar
  • 10 Diamond BJ, Shiflett SC, Feiwel N et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 2000; 81: 668-678
    PubMedGoogle Scholar
  • 11 Appiah-Opong R, Commandeur JN, Axson C et al. Interactions between cytochromes P450, glutathione S-transferases and Ghanaian medicinal plants. Food Chem Toxicol 2008; 46: 3598-3603
    CrossrefPubMedGoogle Scholar
  • 12 Galluzzi S, Zanetti O, Binetti G et al. Coma in a patient with Alzheimer’s disease taking low dose trazodone and gingko biloba. J Neurol Neurosurg Psychiatry 2000; 68: 679-680
    CrossrefPubMedGoogle Scholar
  • 13 EL-Dakhakhny M. Studies on the chemical constituents of Egyptian Nigella sativa L. seeds. The essential oil. Planta Med Planta Med 1963; 11: 465-470
    PubMedGoogle Scholar
  • 14 Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res 2003; 17: 299-305
    CrossrefPubMedGoogle Scholar
  • 15 Basch E, Ulbricht C, Kuo G et al. Therapeutic applications of fenugreek. Altern Med Rev 2003; 8: 20-27
    PubMedGoogle Scholar
  • 16 Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999; 53: 359-365
    CrossrefPubMedGoogle Scholar
  • 17 Balandrin MF, Klocke JA, Wurtele ES et al. Natural plant chemicals: sources of industrial and medicinal materials. Science 1985; 228: 1154-1160
    CrossrefPubMedGoogle Scholar
  • 18 Mahendra P, Bisht S. Ferula asafoetida: Traditional uses and pharmacological activity. Pharmacogn Rev 2012; 6: 141-146
    CrossrefPubMedGoogle Scholar
  • 19 Gupta A, Gupta R, Lal B. Effect of Trigonella foenum-graecum (fenugreek) seeds on glycaemic control and insulin resistance in type 2 diabetes mellitus: a double blind placebo controlled study. J Assoc Physicians India 2001; 49: 1057-1061
    PubMedGoogle Scholar
  • 20 Sabzghabaee AM, Dianatkhah M, Sarrafzadegan N et al. Clinical evaluation of Nigella sativa seeds for the treatment of hyperlipidemia: a randomized, placebo controlled clinical trial. Med Arh 2012; 66: 198-200
    CrossrefPubMedGoogle Scholar
  • 21 Qidwai W, Hamza HB, Qureshi R et al. Effectiveness, safety, and tolerability of powdered Nigella sativa (kalonji) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults: results of a randomized, double-blind controlled trial. J Altern Complement Med 2009; 15: 639-644
    CrossrefPubMedGoogle Scholar
  • 22 Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. Faseb J 2008; 22: 659-661
    PubMedGoogle Scholar
  • 23 Korashy HM, Maayah ZH, Abd-Allah AR et al. Camel milk triggers apoptotic signaling pathways in human hepatoma HepG2 and breast cancer MCF7 cell lines through transcriptional mechanism. J Biomed Biotechnol 2012; 2012: 593195
    PubMedGoogle Scholar
  • 24 Iba MM, Soyka LF, Schulman MP. Characteristics of the liver microsomal drug-metabolizing enzyme system of newborn rats. Mol Pharmacol 1977; 13: 1092-1104
    PubMedGoogle Scholar
  • 25 Lowry OH, Rosebrough NJ, Farr AL et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
    PubMedGoogle Scholar
  • 26 Korashy HM, El-Kadi AO. Differential effects of mercury, lead and copper on the constitutive and inducible expression of aryl hydrocarbon receptor (AHR)-regulated genes in cultured hepatoma Hepa 1c1c7 cells. Toxicology 2004; 201: 153-172
    CrossrefPubMedGoogle Scholar
  • 27 Al-Jenoobi FI. Effects of some commonly used Saudi folk herbal medications on the metabolic activity of CYP2C9 in human liver microsomes. Saudi Pharm J 2010; 18: 167-171
    CrossrefPubMedGoogle Scholar
  • 28 Miners JO, Smith KJ, Robson RA et al. Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem Pharmacol 1988; 37: 1137-1144
    CrossrefPubMedGoogle Scholar
  • 29 Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions. Life Sci 2006; 78: 2105-2115
    CrossrefPubMedGoogle Scholar
  • 30 Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525-538
    CrossrefPubMedGoogle Scholar
  • 31 Chan K, Lo AC, Yeung JH et al. The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995; 47: 402-406
    CrossrefPubMedGoogle Scholar
  • 32 Al-Jenoobi FI, Al-Suwayeh SA, Muzaffar I et al. Effects of Nigella sativa and Lepidium sativum on cyclosporine pharmacokinetics. Biomed Res Int 2013; 2013: 953520
    PubMedGoogle Scholar
  • 33 Al-Mohizea AM, Ahad A, El-Maghraby GM et al. Effects of Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on sildenafil disposition in beagle dogs. Eur J Drug Metab Pharmacokinet 2014;
    PubMedGoogle Scholar
  • 34 Al-Jenoobi FI, Alam MA, Alkharfy KM et al. Pharmacokinetic interaction studies of fenugreek with CYP3A substrates cyclosporine and carbamazepine. Eur J Drug Metab Pharmacokinet 2013;
    PubMedGoogle Scholar
  • 35 Alkharfy KM, Al-Jenoobi FI, Alam MA et al. Lepidium sativum but not Nigella sativa affects carbamazepine disposition in an animal model. Drug Metab Lett 2013; 7: 47-51
    CrossrefPubMedGoogle Scholar
  • 36 Alkharfy KM, Al-Jenoobi FI, Al-Mohizea AM et al. Effects of Lepidium sativum, Nigella sativa and Trigonella foenum-graceum on phenytoin pharmacokinetics in beagle dogs. Phytother Res 2013; 27: 1800-1804
    CrossrefPubMedGoogle Scholar
  • 37 Wang HJ, Pao LH, Hsiong CH et al. Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship. Aaps J 2014; 16: 258-268
    CrossrefPubMedGoogle Scholar
  • 38 Hodek P, Trefil P, Stiborova M. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 2002; 139: 1-21
    CrossrefPubMedGoogle Scholar
  • 39 Jones BC, Hawksworth G, Horne VA et al. Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Drug Metab Dispos 1996; 24: 260-266
    PubMedGoogle Scholar
  • 40 Iranshahy M, Iranshahi M. Traditional uses, phytochemistry and pharmacology of asafoetida (Ferula assa-foetida oleo-gum-resin) – a review. J Ethnopharmacol 2011; 134: 1-10
    CrossrefPubMedGoogle Scholar
  • 41 Miyazawa M, Shindo M, Shimada T. Metabolism of (+)- and (−)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos 2002; 30: 602-607
    CrossrefPubMedGoogle Scholar
  • 42 Si D, Wang Y, Zhou YH et al. Mechanism of CYP2C9 inhibition by flavones and flavonols. Drug Metab Dispos 2009; 37: 629-634
    CrossrefPubMedGoogle Scholar