Study on traditional medicine-modern drug interaction and its molecular mechanism elucidation in rat liver

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Date
1998
Authors
A. Taher, Yousef
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Abstract
Traditional medicines have been used for thousands of years in maintaining health as an alternative to or in conjunction with modem medicines. A majority of the world's population in developing countries take herbal medicine to meet their health needs following low cost traditional beliefs and multiple uses of practice adopted by their elders and ancestors. Most of traditional herbal preparations that we know of today usually comprise of one or more plants in different formulation. Despite their popularity, the active principles, mechanism of action and effectiveness of these preparations remain largely unknown. Nevertheless, they are used widely in Malaysia and other countries. · Many studies have been done to find out the efficacy and side effects of these preparations but most studies used crude extracts or a single purified compound. This does not give a clear picture of its activities as the herbal/traditional preparations are normally concoctions of more than one plant/plant products. It is possible that the effects of traditional preparations are a mixture of effects from all the plants used in the preparation. During the course of therapy, there is concern for some interaction between modem medicine and traditional herbal preparations. The aim of this project is to study the effect of two herbal products sold in the Malaysian market under the name AIR JAMU PAK TANf"> and FAIZOL UBAT BA TUK® on the metabolism of aminopyrine in isolated rat hepatocytes. The influence of factors such as age, sex and diseases (diabetes and hypertension) on the effect of these herbal products on aminopyrine metabolism were also investigated. Diabetes, induced in normal rats using streptozotocin (60 mg/kg, i.v.) and spontaneously hypertensive rats (their blood pressure higher than 160 mmHg) were used to investigate the effect of diabetes and hypertension on aminopyrine metabolism under the influence of these herbal products. In-vitro study was carried out using 6x 103 hepatocytes, 250 mmoi!L aminopyrine and incubation time of 18 minutes. AIR JAMU PAK TANI<.R' or FAIZOL UBA T BA TUK<il' dirutions were added to petri dishes containing aminopyrine, hepatocytes and incubation medium with final volume of 10 mi. In the case of in-vivo study (FAIZOL UBAT BATUK® only) rats were orally fed with several dilutions of FAIZOL UBAT BATUK<R' every 8 hours over a period of one day (acute in-vivo study) and over a period of seven days (sub-acute study) before sacrificed. Termination of the reaction was done by the addition of 25% ZnS04 solution followed by the addition of saturated Ba(OH)2. The absorbance that was measured towards the complex 3,5-diacetyl-1 ,4-dihydrolutidine from the experiment was used to determine the concentration of formaldehyde formed (as metabolite of. aminopyrine) during the experiment which can be used later to be determine the activity of the enzyme aminopyrine N-demethylase. .. To study the molecular mechanism through which these herbal products may influence the metabolism of aminopyrine, certain cellular inhibitors/stimulants were pre-incubated with the hepatocytes for 15 minutes prior to the final incubation of aminopyrine with these herbal products FAIZOL UBAT BATUK® and AIR JAMU PAK TANI'm. In-vitro study of AIR JAMU PAK T AN100 demonstrated that AIR JAMU PAK T ANI® could enhance the N-demethylation of aminopyrine indicating that there is a direct effect of AIR JAMU, PAK TANIOi' on liver aminopyrine metabolism. Effect of AIR JAMU PAK TAN!® on the aminopyrine metabolism was found to be age, sex and disease dependent. Certain second messenger pathways (such as cAMP, cytochrome P4501A2, phosphatase, G-proteins, Ca/CaM-dependent protein kinase and protein tyrosine kinase) were investigated to see the mechanism through which AIR JAMU PAK TANI® could enhance the aminopyrine metabolism. Our data demonstrated that the molecular mechanism of AfR JAMU PAK T ANI® involve various second messenger pathways. This is not surprising since AIR JAMU PAK TANI® consist of more than lO plants and the effect of AIR JAMU PAK T ANI® seen is most probably attributed to the summative effects of all the chemical components found in the whole preparation. In the case of F AIZOL UBA T BA TUK® in-vitro hepatic interaction with aminopyrine resulted in the increase in the metabolism of the latter (most probably ascribed to the total chemical components which consist of at least six plants or plant products). Sex, age and disease factors are found to influence the efTect of FAIZOL USA T BA TUKOi1 on aminopyrine metabolism. ® In-vivo study (acute and sub-acute) of FAIZOL UBAT BATUK may suggest that a possible hepatic interaction with aminopyrine does occur inside the body resulting in increase or decrease in the metabolism of aminopyrine. This hepatic interaction was found to be age, sex and disease dependent. The effect of F AIZOL UBA T BA TUKCR.1 on aminopyrine metabolism seen in-vivo but not in-vitro suggest that FAIZOL UBAT BATUKO:t1 does not have a direct effect on the liver aminopyrine Ndemethylase activity. It's effect on the latter could be via activation--or inhibition of other functioning physiological system. The induction of cytochrome P450 synthesis is possible but remain to be investigated. Both acute and sub-acute in-vivo studies indicate that F AIZOL UBAT BATUK(R' is able to increase phase I aminopyrine metabolism in rat liver. The mechanism through which it is mediated may differ if it is orally administrated over a period of one day or over a period of seven days
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Keywords
Traditional medicine , Rat liver , Drug interaction
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