臺灣博碩士論文加值系統

摘要
乙醯胺酚 (acetaminophen, APAP)是市面上使用最普遍的解熱鎮痛劑。該藥物進入肝臟後，大部分由 phase II 酵素代謝成親水性較高的產物排出，若藥物服用過量，則會有較多的 APAP 由 phase I 酵素 (如：酵素細胞色素 P450, cytochrome P450, CYP)代謝成活性很強的親電子代謝物 NAPQI，NAPQI 可透過麩胱甘肽硫轉移酶與麩胱甘肽 (glutathione, GSH) 結合形成 APAP-GSH 去除活性，消耗體內 GSH，NAPQI 亦會與體內含半胱胺酸之蛋白質結合，使蛋白質結構改變，進而造成肝損傷。檸檬香茅精油(Lemongrass oil)已知有抗氧化及抗發炎等生理活性，然而對於高劑量 APAP 代謝及毒性之影響則未曾被探討。本研究將探討給予大鼠檸檬香茅精油(400 mg/kg B.W.)及其主要成分檸檬醛(240 mg/kg B.W.)對大鼠肝臟乙醯胺酚代謝與毒性之影響。實驗結果：給予大鼠檸檬香茅精油及檸檬醛灌食兩週後大鼠血漿中AST與ALT並無差異。此外，檸檬香茅精油及檸檬醛並不改變肝臟APAP及其代謝物APAP-glutathione、APAP-cysteine與CYP1A2及CYP2E1活性，但會減少APAP-glucuronate、APAP-sulfate含量。此外，檸檬香茅精油及檸檬醛並不改變麩胱甘肽及脂質過氧化物含量。因此以上研究結果顯示檸檬香茅精油及檸檬醛對乙醯胺酚所誘發之肝損傷模式下不具有保護肝臟的效果。

Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. APAP is primarily metabolized in the liver by phase II enzymes to form hydrophilic compounds. When taken overdose, APAP can be also metabolized by phase I enzymes (e.g. cytochrome P450) to form a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which exerts its toxicity by covalent binding to cellular macromolecules such as protein. Lemongrass oil (LO) has been known to have various bioactivities including antioxidant and anti-inflammatory activities. However, the effect of LO on the metabolism and toxicity APAP is still unknown. The present study was to investigate the effect of LO and its major component, citral, on the metabolism and toxicity of acetaminophen in rats. Results show that rats treated with LO and citral for two weeks had no effects on plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. In addition, the concentrations of APAP, APAP-glutathione, APAP-cysteine and the activities of CYP2E1 and CYP1A2 were not changed by LO and citral treatment. In addition, LO and citral had no effect on hepatic glutathione and lipid peroxidation. LO and citral had reduced APAP-glucuronate and APAP-sulfate contents in rat livers. Results from this study suggest that LO and citral may not have a protective effect on APAP-induced liver injury in rats.

目錄
目錄 i
圖目錄 iv
表目錄 v
摘要 1
Abstract 2
第一章、 前言 3
第二章、 文獻探討 5
一、 生物轉換系統(Biotransformation system) 5
(一) 第一期酵素系統(Phase I enzyme system) 6
(二) 第二期結合反應(Phase II conjugation) 11
二、 乙醯胺酚(Acetaminophen; APAP) 15
(一) APAP藥物背景 15
(二) APAP的代謝 16
(三) APAP的毒性 19
三、 檸檬香茅精油與檸檬醛(Lemongrass oil and citral) 20
(一) 檸檬香茅簡介 20
(二) 檸檬香茅的生理功能 21
(三) 檸檬香茅的毒性 23
(四) 檸檬醛簡介 23
(五) 檸檬醛的生理功用 24
(六) 檸檬醛的毒性 24
第三章、 材料與方法 26
一、 實驗架構與流程 26
二、 實驗動物來源 27
三、 檸檬香茅精油來源 27
四、 檸檬香茅精油及檸檬醛灌食液配製 27
五、 動物分組、飼養及樣品收集 28
六、 肝臟微粒體(microsomes)的製備 28
七、 血漿生化指標分析 29
(一) 天門冬胺酸轉胺酶 (Aspartate aminotransaminase；AST) 29
(二) 丙胺酸轉胺酶 (Alanine aminotransaminasea；ALT) 30
八、 肝臟phase I、II酵素及氧化壓力指標的分析 31
(一) CYP酵素活性測定 31
(二) 麩胱苷肽S轉移酶 (Glutathione S-transferase；GST)比活性測定 32
(三) UDP-glucuronosyltransferase (UGT)活性測定 32
(四) Sulfotransferase (ST)活性測定 32
(五) 麩胱苷肽 (GSH/GSSG)含量及抗氧化系統比活性測定 33
(六) 肝臟自由基(ROs)含量測定 34
(七) 肝臟脂質過氧化物(Thiobarbituric acid-reactive substances；TBARs)測定 34
九、 肝臟及血漿中APAP及其代謝物濃度測定 35
十、 統計方法 36
第四章、 結果與討論 37
一、 對大鼠體重及肝臟腎臟的影響： 37
二、對血漿中肝功能指標的影響： 37
三、肝臟中抗氧化系統的改變： 38
四、肝臟中APAP及其代謝物濃度之影響： 39
五、肝臟中Phase I 及Phase II酵素系統之活性： 40
第五章、 結論 46
第六章、 參考文獻 47

圖目錄
圖2- 1、生物轉換系統 6
圖2- 2、體內外來物質經CYP循環代謝 7
圖2- 3、人類肝臟中參與藥物代謝之CYP含量比例 9
圖2- 4、葡萄醣醛酸結合反應圖 12
圖2- 5、Sulfotransferase催化的sulfation反應圖 13
圖2- 6、Glutathione conjugation 代謝反應 14
圖2- 7、肝臟 acetaminophen的代謝路徑圖 18
圖2- 8、體內acetaminophen 代謝圖 19

表目錄
表2- 1、人類CYP酵素之分佈位置、受質及誘導物……………...10
表3- 1、CYP酵素受質濃度及其代謝物............................................31
表4- 1、給予檸檬香茅精油及檸檬醛兩週後對大鼠體重及組織重的影響....................................................................................... 41
表4- 2、給予檸檬香茅精油及檸檬醛兩週再腹腔注射APAP後血漿中肝功能指標的變化 42
表4- 3、給予檸檬香茅精油及檸檬醛兩週再腹腔注射APAP後肝臟中之抗氧化防禦系統 43
表4- 4、給予檸檬香茅精油及檸檬醛兩週再腹腔注射APAP後肝臟中APAP及其代謝物之濃度 44
表4- 5、給予檸檬香茅精油及檸檬醛兩週再腹腔注射APAP後肝臟中藥物代謝酵素活性 45

游士儒 (2010). Acetaminophen 藥物過量之治療. 耕莘藥訊 49: 1-7.

賴國誌, 廖永智, 林美智, 顧祐瑞, 蔡麗瑤, 李蕙君, 范振一, 王依婷, 劉宜祝, 林哲輝, 羅吉方 (2010). 九十八年度調製劑中藥檢出西藥情形之分析. 食品藥物研究年報 1: 212-223.

賴國誌, 廖永智, 林美智, 顧祐瑞, 徐雅慧, 蔡麗瑤, 李蕙君, 呂康祖, 劉宜祝, 羅吉方 (2011). 九十九年調製劑中藥檢出西藥成分之分析. 食品藥物研究年報 2: 339-349.

姜紹青 (2014). 如何服用止痛藥才安全？康健雜誌 189

張峻華 (2014). 檸檬香茅精油與檸檬醛對大鼠肝臟藥物代謝酵素與抗氧化系統之影響.中國醫藥大學營養學系碩士班碩士論文, 1-63



Acharya M., Lau Cam C. A. (2010). Comparison of the protective actions of N-acetylcysteine, hypotaurine and taurine against acetaminophen-induced hepatotoxicity in the rat. J Biomed Sci 17:35-46.

Adams J. D., Lauyerburg B.H., Mitchell J.R. (1983). Plasma glutathione and glutathione disulfide in the rat regulation and response to oxidative stress. J Pharmacol Exp Ther 227:749-754.

Adegbegi, J. A., I. B. O. Dada, O. E. Seyifunmi and S. O. Bada (2015). Nephroprotective effect of aqueous extract of Cymbopogon citratus (lemon grass) in Wistar albino rats.Int J Pharm Biomed Res.

Adikay, S. and S. thodupunoori (2015). Pharmacological evaluation of anti-ulcer activity of Cymbopogon flexuosus. International Journal of Basic & Clinical Pharmacology 4(2):208-212

Adukwu, E. C., S. C. Allen and C. A. Phillips (2012). The anti-biofilm activity of lemongrass (Cymbopogon flexuosus) and grapefruit (Citrus paradisi) essential oils against five strains of Staphylococcus aureus.J Appl Microbiol 113(5): 1217-1227.

Allameh, A., and Alikhani, N. (2002). Acetaminophen-glutathione conjugate formation in a coupled cytochrome P-450-glutathione S-transferase assay system mediated by subcellular preparations from adult and weanling rat tissues. Toxicol In Vitro 16(6): 637-641.

Aleksunes L.M., Augustine L.M., Cherrington N.J., Manautou J.E. (2007). Influence of acetaminophen vehicle on regulation of transporter gene expression during hepatotoxicity. Journal of toxicology and environmental health Part A 70:1870-1872.
Allameh A., and Alikhani N. (2002). Acetaminophen-glutathione conjugate formation in a coupled cytochrome P-450-glutathione S-transferase assay system mediated by subcellular preparations from adult and weanling rat tissues. Toxicology in vitro 16:637-641.

Anzenbacher P., and Anzenbacherova E. (2001). Cytochromes P450 and metabolism of xenobiotics. Cellular and Molecular Life Sciences 58:737-747.

Bae, O. N., S. Ahn, S. H. Jin, S. H. Hong, J. Lee, E. S. Kim, T. C. Jeong, Y. J. Chun, A. Y. Lee and M. Noh (2015). Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.Toxicol Appl Pharmacol 283(2): 147-155.


Bessems, J. G., and Vermeulen, N. P. (2001). Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 31(1): 55-138.

Boukhatem, M. N., M. A. Ferhat, A. Kameli, F. Saidi and H. T. Kebir (2014). Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs.Libyan J Med 9: 25431.

Boyd E.M., Bereczky G. M. (1966). Liver necrosis from paracetamol. Br J Pharmacol Chemother 26:606-614.

Brian, T. S. and A. K. Ikhlas (2002). Comparison of Extraction Methods for Marker Compounds in the Essential Oil of Lemon Grass by GC.J. Agric. Food Chem.(50): 1345.

Brunton L.L., Lazo J. S., and K.L., P. (2006). Goodman & Gilman''s The Pharmacological Basis of Therapeutics 11th.


Burchell B., Brierley C. H., Rance D (1995). Specificity of human UDP-Glucuronosyltransferases and xenobiotic glucuronidation. Life Sciences 57:1819-1995.

Caballero-Gallardo, K., J. Olivero-Verbel and E. E. Stashenko (2012). Repellency and toxicity of essential oils from Cymbopogon martinii, Cymbopogon flexuosus and Lippia origanoides cultivated in Colombia against Tribolium castaneum.Journal of Stored Products Research 50: 62-65.

Carriere, V., Chambaz, J., and Rousset, M. (2001). Intestinal responses to xenobiotics. Toxicol In Vitro 15(4-5): 373-378.


Chalasani N., Fontana R. J., Bonkovsky H. L., Watkins P. B., Davern T, Serrano J, Yang H., Rochon J (2008). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924-1934, 1934 e1921-1924.

Chen, C., Hennig, G. E., and Manautou, J. E. (2003). Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR-) hyperbilirubinemic rats. Drug Metab Dispos 31(6): 798-804.

Chen, X., Baker, S. M., and Chen, G. (2005). Methotrexate induction of human sulfotransferases in Hep G2 and Caco-2 cells. J Appl Toxicol 25(5): 354-360.

Chen, X., Sun, C. K., Han, G. Z., Peng, J. Y., Li, Y., Liu, Y. X., Lv, Y. Y., Liu, K. X., Zhou, Q., and Sun, H. J. (2009). Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significantly correlated with cytochrome P450 suppression. World J Gastroenterol 15(15): 1829-1835.

Cheng, J. W., Frishman, W. H., and Aronow, W. S. (2010). Updates on cytochrome p450-mediated cardiovascular drug interactions. Dis Mon 56(3): 163-179.

Christopher, E., D. Nyebuk and A. Ernest (2014). Phytoconstituents and diuretic activity of Cymbopogon citratus leaf infusions in humans.Journal of Coastal Life Medicine 2(9): 704-713.

Christopher, E. E., E. A. Ernest and E. D. Nyebuk (2014). Phytochemical Constituents, Therapeutic Applications and Toxicological Profile of Cymbopogon citratus Stapf (DC) Leaf Extract.3(1): 131-141.



Christopher, E. E., D. Koofreh and E. A. Ekaette (2014). Cymbopogon citratus Stapf (DC) Extract Ameliorates Atherogenic Cardiovascular Risk in Diabetes-Induced Dyslipidemia in Rats. British Journal of Medicine & Medical Research 4(28): 4695-4709.

Coles B., Wilson I., Wardman P., Hinson J. A., Nelson S. D., Ketterer B. (1988). The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Archives of biochemistry and biophysics 264:253-260.

Corcoran G. B., Racz W. J., Smith C. V., and Mitchell J. R. (1985). Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice. J Pharmacol Exp Ther 232:864-872.

Costa, C. A., L. T. Bidinotto, R. K. Takahira, D. M. Salvadori, L. F. Barbisan and M. Costa (2011). Cholesterol reduction and lack of genotoxic or toxic effects in mice after repeated 21-day oral intake of lemongrass (Cymbopogon citratus) essential oil.Food Chem Toxicol 49(9): 2268-2272.

Costa, G., S. Gonzalez-Manzano, A. Gonzalez-Paramas, I. V. Figueiredo, C. Santos-Buelga and M. T. Batista (2015). Flavan hetero-dimers in the Cymbopogon citratus infusion tannin fraction and their contribution to the antioxidant activity.Food Funct 6(3): 932-937.

Coughtrie, M. W. (2002). Sulfation through the looking glass--recent advances in sulfotransferase research for the curious. Pharmacogenomics J 2(5): 297-308.

Das J., Ghosh J., Manna P., Sil P. C. (2010). Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology 269:24-34.

de Vries, J. (1981). Hepatotoxic metabolic activation of paracetamol and its derivatives phenacetin and benorilate: oxygenation or electron transfer Biochem Pharmacol 30(5): 399-402.

Dierickx P. J. (1994). The influence of picolines on glutathione transferase activity and subunit composition in human liver derived Hep G2 cells. Biochem Pharmacol 48:1976-1978.

Faber, K. N., Muller, M., and Jansen, P. L. M. (2003). Drug transport proteins in the liver. Adv Drug Deliv Rev 55: 107-124.

Farah, I. O., C. Holt Gray, J. A. Cameron, M. A. Tucci, Z. Cason and H. A. Benghuzzi (2014). Impact of paired combinations of retinoic Acid (atra) and ovalbumin on f344 rat lung tissues and improvement of related pathology by citral. Biomed Sci Instrum(50): 423-430.

Francisco, V., A. Figueirinha, B. M. Neves, C. Garcia-Rodriguez, M. C. Lopes, M. T. Cruz and M. T. Batista (2011). Cymbopogon citratus as source of new and safe anti-inflammatory drugs: bio-guided assay using lipopolysaccharide-stimulated macrophages.J Ethnopharmacol 133(2): 818-827.

Fontana, R. J. (2008). Acute liver failure including acetaminophen overdose. Med Clin North Am 92(4): 761-794, viii.

Gardner C. R., Laskin J. D., Dambach D. M., Sacco M., Durham S. K., Bruno M. K., Cohen S. D., Gordon M. K., Gerecke D. R., Zhou P., Laskin D. L. (2002). Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: potential role of tumor necrosis factor-alpha and interleukin-10. Toxicol Appl Pharmacol 184:27-36.



Ghanem, C. I., Ruiz, M. L., Villanueva, S. S., Luquita, M. G., Catania, V. A., Jones, B., Bengochea, L. A., Vore, M., and Mottino, A. D. (2005). Shift from biliary to urinary elimination of acetaminophen-glucuronide in acetaminophen-pretreated rats. J Pharmacol Exp Ther 315(3): 987-995.

Glatt, H., and Meinl, W. (2004). Pharmacogenetics of soluble sulfotransferases (SULTs). Naunyn Schmiedebergs Arch Pharmacol 369(1): 55-68.

Golestan Jahromi M., Nabavizadeh F., Vahedian J., Nahrevanian H., Dehpour A. R., Zare-Mehrjardi A. (2010). Protective effect of ghrelin on acetaminophen-induced liver injury in rat. Peptides 31:2114-2117.

Gonzalez, F. J., and Gelboin, H. V. (1994). Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metabolism Reviews 26(1-2): 165-183.

Grancharov, K., Naydenova, Z., Lozeva, S., and Golovinsky, E. (2001). Natural and synthetic inhibitors of UDP-glucuronosyltransferase. Pharmacol Ther 89(2): 171-186.

Guengerich, F. P. (1994). Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett 70(2): 133-138.

Guengerich F. P. (1997). Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol 43:7-35.

Hagvall, L., J. M. Baron, A. Borje, L. Weidolf, H. Merk and A. T. Karlberg (2008). Cytochrome P450-mediated activation of the fragrance compound geraniol forms potent contact allergens.Toxicol Appl Pharmacol 233(2): 308-313.


Harris, R. Z., Jang, G. R., and Tsunoda, S. (2003). Dietary effects on drug metabolism and transport. Clin Pharmacokinet 42(13): 1071-1088.

Henderson C. J., Wolf C. R., Kitteringham N., Powell H., Otto D., Park B. K. (2000). Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proceedings of the National Academy of Sciences of the United States of America 97:12741-12745.

Hinson, J. A., Reid, A. B., McCullough, S. S., and James, L. P. (2004). Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 36(3-4): 805-822.

Jaeschke H., Bajt M. L. (2006). Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31-41.

Jaeschke H., Knight T. R., Bajt M. L. (2003). The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 144:279-288.

James, L. P., Mayeux, P. R., and Hinson, J. A. (2003). Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 31(12): 1499-1506.
Jancova, P., Anzenbacher, P., and Anzenbacherova, E. (2010). Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154(2): 103-116.

Jetten, M. J., Gaj, S., Ruiz-Aracama, A., de Kok, T. M., van Delft, J. H., Lommen, A., van Someren, E. P., Jennen, D. G., Claessen, S. M., Peijnenburg, A. A., Stierum, R. H., and Kleinjans, J. C. (2012). ''Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans. Toxicol Appl Pharmacol 259(3): 320-328.

Kawanishi, S., Oikawa, S., and Murata, M. (2005). Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal 7(11-12): 1728-1739.

Kim, K. A., Lee, J. S., Park, H. J., Kim, J. W., Kim, C. J., Shim, I. S., Kim, N. J., Han, S. M., and Lim, S. (2004). Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sciences 74(22): 2769-2779.

King, C. D., Rios, G. R., Green, M. D., and Tephly, T. R. (2000). UDP-glucuronosyltransferases. Curr Drug Metab 1(2): 143-161.

Kobayashi, K., Urashima, K., Shimada, N., and Chiba, K. (2002). Substrate specificity for rat cytochrome P450 (CYP) isoforms: screening with cDNA-expressed systems of the rat. Biochemical Pharmacology 63(5): 889-896.

Koh, P. H., R. A. Mokhtar and M. Iqbal (2012). Antioxidant potential of Cymbopogon citratus extract: alleviation of carbon tetrachloride-induced hepatic oxidative stress and toxicity.Hum Exp Toxicol 31(1): 81-91.

Koppaka, V., D. C. Thompson, Y. Chen, M. Ellermann, K. C. Nicolaou, R. O. Juvonen, D. Petersen, R. A. Deitrich, T. D. Hurley and V. Vasiliou (2012). Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.Pharmacol Rev 64(3): 520-539.

Kostrubsky V. E., Szakacs J. G., Jeffery E. H., Wood S. G., Bement W. J., Wrighton S. A., Sinclair P. R., Sinclair J. F. (1997). Role of CYP3A in ethanol-mediated increases in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 143:315-323.

Kozer, E., and Koren, G. (2001). Management of paracetamol overdose: current controversies. Drug Saf 24(7): 503-512.

Kumar, A., F. Malik, S. Bhushan, V. K. Sethi, A. K. Shahi, J. Kaur, S. C. Taneja, G. N. Qazi and J. Singh (2008). An essential oil and its major constituent isointermedeol induce apoptosis by increased expression of mitochondrial cytochrome c and apical death receptors in human leukaemia HL-60 cells.Chem Biol Interact 171(3): 332-347.

Kuo, C. H., S. H. Lee, K. M. Chen, C. K. Lii and C. T. Liu (2011). Effect of garlic oil on neutrophil infiltration in the small intestine of endotoxin-injected rats and its association with levels of soluble and cellular adhesion molecules. J Agric Food Chem 59(14): 7717-7725.

Laine J. E., Auriola S., Pasanen M., Juvonen R. O. (2009). Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica; the fate of foreign compounds in biological systems 39:11-21.

Lash, L. H., Putt, D. A., Huang, P., Hueni, S. E., and Parker, J. C. (2007). Modulation of hepatic and renal metabolism and toxicity of trichloroethylene and perchloroethylene by alterations in status of cytochrome P450 and glutathione. Toxicology 235(1-2): 11-26.


Li, J., Kaneko, T., Wang, Y., Qin, L. Q., Wang, P. Y., and Sato, A. (2002). Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. Toxicology 176(1-2): 91-100.

Li, R. Y., X. M. Wu, X. H. Yin, Y. H. Long and M. Li (2015). Naturally produced citral can significantly inhibit normal physiology and induce cytotoxicity on Magnaporthe grisea. Pestic Biochem Physiol 118: 19-25.



Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., Iyanagi, T., Lancet, D., Louisot, P., Magdalou, J., Chowdhury, J. R., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. F., and Nebert, D. W. (1997a). The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7(4): 255-269.


Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., Iyanagi, T., Lancet, D., Louisot, P., Magdalou, J., Chowdhury, J. R., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. F., and Nebert, D. W. (1997b). The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7(4): 255-269.

Maiti, S., Chen, X., and Chen, G. (2005). All-trans retinoic acid induction of sulfotransferases. Basic Clin Pharmacol Toxicol 96(1): 44-53.

Martinez-Jimenez, C. P., Jover, R., Donato, M. T., Castell, J. V., and Gomez-Lechon, M. J. (2007). Transcriptional regulation and expression of CYP3A4 in hepatocytes. Curr Drug Metab 8(2): 185-194.

McGill, M. R., Williams, C. D., Xie, Y. C., Ramachandran, A., and Jaeschke, H. (2012). Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol 264(3): 387-394.

Mitra, A., Kulkarni,A. P., Ravikumar, V. C., Bourcier, D. R., (1991). Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen. Journal of Biochemical and Molecular Toxicology 6: 93-100

Mohamed Hanaa, A. R., Y. I. Sallam, A. S. El-Leithy and S. E. Aly (2012). Lemongrass (Cymbopogon citratus) essential oil as affected by drying methods. Annals of Agricultural Sciences 57(2): 113-116.

Mohd, I. N., A. F. Bashir, J. Ebenezar and A. B. Javid (2010). Antibacterial activity of lemongrass (Cymbopogon citratus) oil against some selected pathogenic bacterias.APJTM 3(7): 535-538.


Morel, F., Langouet, S., Maheo, K., and Guillouzo, A. (1997). The use of primary hepatocyte cultures for the evaluation of chemoprotective agents. Cell Biol Toxicol 13(4-5): 323-329.

Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., Gunsalus, I. C., and Nebert, D. W. (1996). P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6(1): 1-42.

Nugon-Baudon, L., Roland, N., Flinois, J. P., and Beaune, P. (1996). Hepatic cytochrome P450 and UDP-glucuronosyl transferase are affected by five sources of dietary fiber in germ-free rats. J Nutr 126(2): 403-409.

Peters, L. P., and Teel, R. W. (2003). Effects of high sucrose diet on body and liver weight and hepatic enzyme content and activity in the rat. In Vivo 17(1): 61-65.
Porto Mde, P., G. N. da Silva, B. C. Luperini, T. F. Bachiega, J. P. de Castro Marcondes, J. M. Sforcin and D. M. Salvadori (2014). Citral and eugenol modulate DNA damage and pro-inflammatory mediator genes in murine peritoneal macrophages.Mol Biol Rep 41(11): 7043-7051.


Prescott, L. F. (1980). Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 10 Suppl 2: 291-298.

Reith, D., Medlicott, N. J., Kumara De Silva, R., Yang, L., Hickling, J., and Zacharias, M. (2009). Simultaneous modelling of the Michaelis-Menten kinetics of paracetamol sulphation and glucuronidation. Clin Exp Pharmacol Physiol 36(1): 35-42.

Rendic S. (2002). Summary of information on human CYP enzymes: human P450 metabolism data. Drug metabolism reviews 34:83-448.

Ritter, J. K. (2000). Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact 129(1-2): 171-193.

Rousar, T., Nydlova, E., Cesla, P., Stankova, P., Kucera, O., Parik, P., and Cervinkova, Z. (2012). Purified acetaminophen-glutathione conjugate is able to induce oxidative stress in rat liver mitochondria. Physiol Res 61 Suppl 2: S103-109.

Salinas, A. E., and Wong, M. G. (1999). Glutathione S-transferases--a review. Curr Med Chem 6(4): 279-309.

Saxena, S., V. Uniyal and R. P. Bhatt (2012). Inhibitory effect of essential oils against Trichosporon ovoides causing Piedra Hair Infection.Braz J Microbiol. 43(4): 1347-1354.

Slaughter R. L., Edwards D. J. (1995). Recent advances: the cytochrome P450 enzymes. The Annals of pharmacotherapy 29:619-624.



Sinclair J. F, Szakacs J. G, Wood S. G, Walton H. S, Bement J. L, Gonzalez F. J, Jeffery E. H, Wrighton S. A, Bement W. J, and Sinclair P. R (2000) Short-term treatment with alcohols causes hepatic steatosis and enhances acetaminophen hepatotoxicity in Cyp2e1(-/-) mice. Toxicology and applied pharmacology 168: 114-122.

Sharma, P. R., D. M. Mondhe, S. Muthiah, H. C. Pal, A. K. Shahi, A. K. Saxena and G. N. Qazi (2009). Anticancer activity of an essential oil from Cymbopogon flexuosus.Chem Biol Interact 179(2-3): 160-168.

Sheweita, S. A. (2000). Drug-metabolizing enzymes: mechanisms and functions. Curr Drug Metab 1(2): 107-132.

Sorensen, J. M. (2002). Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: Mechanisms involved and their medical implications. Journal of Alternative and Complementary Medicine 8(3): 293-308.

Sugatani J., Wada T., Osabe M., Yamakawa K., Yoshinari K., Miwa M. (2006). Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4alpha expression. Drug Metab Dispos 34:1677-1687.

Sugiyama, T., Kubota, Y., Shinozuka, K., Yamada, S., Wu, J., and Umegaki, K. (2004). Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytochrome P450 mediated mechanism in aged rats. Life Sciences 75(9): 1113-1122.

Szaefer, H., Jodynis-Liebert, J., Cichocki, M., Matuszewska, A., and Baer-Dubowska, W. (2003). Effect of naturally occurring plant phenolics on the induction of drug metabolizing enzymes by o-toluidine. Toxicology 186(1-2): 67-77.

Talalay P. (2000). Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12:5-11.

Tan S. C., New L. S., Chan E. C. (2008). Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine. Toxicol Lett 180:174-181.

Testa B., Pedretti A., Vistoli G. (2012). Reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug discovery today 17:549-560.

Tonoli, D., Varesio, E., and Hopfgartner, G. (2012). Quantification of acetaminophen and two of its metabolites in human plasma by ultra-high performance liquid chromatography-low and high resolution tandem mass spectrometry. J Chromatography B 904: 42-50.

Uzama, D., R. Ahmadu, B. M. David and S. A. Thomas (2011). Comparative study on the Antimicrobial activities of the Ethanolic extracts of Lemon grass and Polyalthia Longifolia. Journal of Applied Pharmaceutical Science 09: 174-176.

van Bladeren, P. J. (2000). Glutathione conjugation as a bioactivation reaction. Chem Biol Interact 129(1-2): 61-76.

Vinutha, M., K. S. Tulsi Naik, R. Pavan, M. N. Shivakameshwari and K. J. Thara Saraswathi (2014). Essential oil studies and RAPD markers in sUV-B treated Cymbopogon flexuosus (Nees ex Steud) wats.International Journal of Biosciences (IJB) 4(1): 365-371.

Walsky, R. L., and Obach, R. S. (2004). Validated assays for human cytochrome P450 activities. Drug Metab Dispos 32(6): 647-660.


Yamazaki, H., Nakajima, M., Nakamura, M., Asahi, S., Shimada, N., Gillam, E. M., Guengerich, F. P., Shimada, T., and Yokoi, T. (1999). Enhancement of cytochrome P-450 3A4 catalytic activities by cytochrome b(5) in bacterial membranes. Drug Metab Dispos 27(9): 999-1004.

Yao, H. T., Chang, Y. W., Lan, S. J., and Yeh, T. K. (2008). The inhibitory effect of tannic acid on cytochrome P450 enzymes and NADPH-CYP reductase in rat and human liver microsomes. Food Chem Toxicol 46(2): 645-653.

Yao, H. T., Lii, C. K., Chou, R. H., Lin, J. H., Yang, H. T., and Chiang, M. T. (2010). Effect of chitosan on hepatic drug-metabolizing enzymes and oxidative stress in rats fed low- and high-fat diets. J Agric Food Chem 58(8): 5187-5193.

Yao, H. T., Lin, P., Chang, Y. W., Chen, C. T., Chiang, M. T., Chang, L., Kuo, Y. C., Tsai, H. T., and Yeh, T. K. (2009). Effect of taurine supplementation on cytochrome P450 2E1 and oxidative stress in the liver and kidneys of rats with streptozotocin-induced diabetes. Food Chem Toxicol 47(7): 1703-1709.

Yanpallewar B. M. (2010). Dose-dependent hepatoprotective effect of emodin against acetaminophen-induced acute damage in rats. Exprimental and Toxicologic Pathology 62: 627-35.

Zaher, H., Buter, J. T., Ward, J. M., Bruno, M. K., Lucas, A. M., Sterm, S. T., Cohen, S. D., Gonzalez, F. J. (1998). Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 Double-null mice. Toxicology and Applied Pharmacology, 152(1): 193-199

Zheljazkov, V. D., C. L. Cantrell, T. Astatkie and J. B. Cannon (2011). Lemongrass Productivity, Oil Content, and Composition as a Function of Nitrogen, Sulfur, and Harvest Time.Agronomy Journal 103(3): 805.


Zheng, S., G. Jing, X. Wang, Q. Ouyang, L. Jia and N. Tao (2015). Citral exerts its antifungal activity against Penicillium digitatum by affecting the mitochondrial morphology and function.Food Chem 178: 76-81.