In vitro effects of Air Jamu Pak Tani, an herbal product, on aminopyrine hepatic phase I n-demethylase activity in spontaneous hypertensive rats: the mechanism involved
DOI:
https://doi.org/10.54361/LJMR.19.2.23Keywords:
Drug metabolism, Hepatocytes, Aminopyrine, Herbal product, Cytochrome 450Abstract
Objective: Pharmacokinetic interactions of co-administered herbal isolates with pharmaceuticals and the mechanisms of interactions remain to be elucidated. Herein, we evaluated the in vitro effects of Air Jamu Pak Tani (AJPT), a mixture of plant isolates, on phase I aminopyrine metabolism and the molecular mechanism involved in spontaneous hypertensive rat (SHR) livers. Material and Methods: Hepatocytes were isolated by the collagenase perfusion technique. Aminopyrine n-demethylase activity was determined using the colorimetric method of Nash. Results: Compared to control AJPT dose independently increased significantly the aminopyrine n-demethylase activity by 29.6% (P<0.05). Molecular mechanism elucidation, using protein stimulants (or inhibitors), showed that the effect of AJPT was significantly abrogated by the pre-incubation of hepatocytes with 3-isobutyl-methylxanthine and okadaic acid. Trifluoperazine and genistein did not change the effect of AJPT, while no significant observation was verified in the presence of guanylyl-5’-imidodiphosphate and furafylline. In conclusion, administration of AJPT induced dephosphorylation of cytochrome P450 in young male SHR hepatocytes. The effect of AJPT was mediated through different molecular mechanisms, most probably, including inhibition of tyrosine kinases, calmodulin, and cAMP/PKA pathways, and also due to activation of protein phosphatases. Therefore, caution should be considered when AJPT is used with n-demethylase substrate ‘drugs’ as it may reduce their bioavailability.
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1. Hodgson E, Goldstein JA. Metabolism of toxicants: Phase I reactions and pharmacogenetics. In Hodgson E. and Smart RC. (eds.). Introduction to biochemical toxicology. New York: Wiley Interscience. 2001; 67-96.
2. Briggs DR. The regulation of herbal medicines in Australia. Toxicology. 2002; 181-182:565-70.
3. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of herbs with cytochrome P450. Drug Metab. Rev. 2003; 35:35-98.
4. Purwantiningsih, Hussin AH, Chan KL. Effect of standardized Eurycoma longifolia extract on rosiglitazone metabolism in the old normal male rat hepatocytes: a mechanism study. International Journal of
Pharmaceutical Sciences and Research. 2015; 6(5) 2163-69.
5. Anwar R, Hussin AH, Ismail S, Mansor SM. In vitro effect of mitragynine on activity of drug metabolizing enzymes, n-demethylase and glutathione s-transferase in streptozotocin-induced diabetic rats. Pharmacoloyonline. 2012; 1:68-75.
6. Chin JH, Hussin AH. Effect of the Orthosiphon stamineus, Benth on aminopyrine metabolism in rat hepatocytes. Malaysian Journal of Pharmaceutical Sciences. 2007; 5(1):25-32.
7. Han CJ, Hussin AH, Ismail S. Effect of methanol leaf extract of Orthosiphon stamineus Benth. on hepatic drug metabolizing enzymes in Sprague Dawley (SD) rats. Journal of Bioscience. 2008; 19(1):21-31.
8. Mahfoudh M, Ismail N, Ismail S, Hussin AH. In vitro ex vivo assessment of Morinda citrifolia on drug metabolizing enzymes in spontaneously hypertensive rats. Pharmaceutical Biology. 2009; 47(12):1108–16.
9. Taher YA, Hussin AH. In vivo effects of Faizol Ubat Batuk, a herbal product on aminopyrine metabolism in rat hepatocytes. Libyan J. Med. 2011; 6:1-5.
10. Purwantiningsih, Hussin AH, Chan KL. Sex-related alterations of aminopyrine metabolism by standardized extract of Eurycoma longifolia (TAF-273). Acta Alimentaria. 2012; 41(3):316–26.
11. Merrick BA, Davies MH, Cook DE, Holcslaw TL, Schnell RC. Alterations in hepatic microsomal drug metabolism and cytochrome P-450 proteins in spontaneously hypertensive rats. Pharmacology. 1985; 30:129-35.
12. Nash T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem. J. 1953; 55:416-21.
13. Canivenc-Lavier MC, Vernevaut MF, Totis M, Siess MH, Magdalou J, Suschetet M. Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver. Toxicology. 1996; 114:19-27.
14. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J. Psychopharmacol. 2004; 18:262-76.
15. Gibson GG, Skett P. Introduction to drug metabolism. 3th ed. Cheltenham: Nelson Thornes Publishers. 2001.
16. Timbrell J. Principles of biochemical toxicology. London: Taylor and Francis Ltd. 2001.
17. Pavithra BH, Prakash N, Jayakumar K. Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits. J. Vet. Sci. 2009; 10:293-97.
18. Salman SA, Amrah S, Wahab MS, Ismail Z, Ismail R, Yuen KH, Gan SH. odification of propranolol's bioavailability by Eurycoma longifolia water-based extract. J. Clin. Pharm. Ther. 2010; 35:691-96.
19. Oesch-Bartlomowicz B, Oesch F. Phosphorylation of cytochromes P450: first discovery of a posttranslational modification of a drug-metabolizing enzyme. Biochem. Biophys. Res. Commun. 2005; 338:446-49.
20. Dombradi V. Structure and function of protein phosphatases. Eur. J. Biochem. 2002; 269:1049.
21. Huai Q, Wang H, Zhang W, Colman RW, Robinson H, Ke H. Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding. Proc. Natl. Acad. Sci. USA. 2004; 101:9624-29.
22. Hube F, Lee YM, Rohrig K, Hauner H. The phosphodiesterase inhibitor IBMX suppresses TNF-alpha expression in human adipocyte precursor cells: a possible explanation for its adipogenic effect. Horm. Metab. Res. 1999; 31:359-62.
23. Grief F, Soroff HS, Albers KM, Taichman LB. The effect of trifluoperazine, a calmodulin antagonist, on the growth of normal and malignant epidermal keratinocytes in culture. Eur. J. Cancer Clin. Oncol. 1989; 25:19-26.
24. Bialojan C, Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem. J. 1988; 256:283-90.
25. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987; 262:5592-95.
26. Sesardic D, Boobis AR, Murray BP, Murray S, Segura J, de la Torre R, Davies DS. Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man. Br. J. Clin. Pharmacol. 1990; 29:651-63.
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