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Digestions and Detoxification By

Digestions and Detoxification By Stephen Eddey M.H.Sc.,B.H.Sc.,Dip.App.Sc.,Ass.Dip.App.Sc.,Cert.I.V.(Workplace and Training). Principal Health Schools Australia. Digestion - Stomach.

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Digestions and Detoxification By

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  1. Digestions and Detoxification By Stephen Eddey M.H.Sc.,B.H.Sc.,Dip.App.Sc.,Ass.Dip.App.Sc.,Cert.I.V.(Workplace and Training). Principal Health Schools Australia

  2. Digestion - Stomach Acid is the key to optimal stomach digestion. Arginine boost blood flow to the stomach and increases stomach acid. Brzozowski, T., et al. Role of L-arginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing. Journal of Gastroenterology. 32(4):442-452, 1997.

  3. Glutamine Boosts Stomach acids These results show that a Gln-enriched enteral diet increased splanchnic blood flow, which was not mediated by pancreatic glucagon or increased nitric oxide production as determined by urinary nitrate excretion. Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic blood flow in the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.

  4. Ginger Protects the Stomach “The results of this study demonstrate that the extract in the dose of 500 mg/kg orally exert highly significant cytoprotection against 80% ethanol, 0.6M HC1, 0.2M NaOH and 25% NaCl induced gastric lesions. The extract also prevented the occurrence of gastric ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs) and hypothermic restraint stress. These observations suggest cytoprotective and anti-ulcerogenic effect of the ginger.” Al-Yahya, M. A., et al. Gastro protective activity of ginger in albino rats. Am J Chinese Med. 17(1-2):51-56, 1989.

  5. Glutamine Increases Blood Flow to the Pancreas “In the glutamine-enriched group, higher organ blood flows were measured in the stomach (51%), the pancreas (35%), small intestine (32%), and colon (55%), compared with controls. No differences were found in systemic hemodynamic parameters between the control and Gln-supplemented groups. Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic blood flow in the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.

  6. The Liver: Why is it so big?

  7. Biotransformation Biotransformation is the metabolic alteration of toxins and other chmicals by phase 1 (cytochrome P450) and phase 2 (conjugating) enzymes. These enzymes are involved in both the synthesis of steroid hormones, and the clearance (detoxification) of harmful endogenous and exogenous compounds.

  8. Biotransformational activation of substrates “Human beings are faced with a continuous burden of reactive chemical entities that are formed during biotransformation of foreign compounds, as well as from endogenous molecules.” Rinaldi R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metab Disp. 2002;30:1053-1058.

  9. Biotransformational activation of substrates “Many developmental toxicants and teratogens require prior metabolism to reactive species or free radicals to exert toxicity. Thus the knowledge of conceptal biotransformation is absolutely critical in understanding toxicity of these chemicals” Kulkarni AP. Role of biotransformation in conceptal toxicity of drugs and other chemicals. Curr Pharm Des. 2001 Jun;7(9):833-57.

  10. BIOTRANSFORMATION IS A PROTECTIVE MECHANISM “Along with strategies such as sequestration, scavenging and binding, catalytic biotransformation evolved as an important biochemical protection mechanism against toxic chemical species.” Sheehan D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 2001;360:1-16

  11. ENZYMES MEDIATE BIOTRANSFORMATION “Cells possess an impressive array of enzymes capable of biotransforming a wide range of different chemical structures and functionalities.” Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

  12. BIOTRANSFORMATION IS IMPERATIVE FOR SURVIVAL The perpetuation of human and other animal species depends, among other factors, on successful defence against the deleterious effects of naturally occurring toxic chemicals in plants and synthetic toxicants.” Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825

  13. UNDERSTANDING BIOTRANSFORMATION IMPROVES DRUG THERAPY “biotransformation represents a key element in understanding the pharmacological efficacy of drugs and the toxicity (of) pesticides, industrial/ environmental chemicals, and naturally occurring toxicants” Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825

  14. THE PHASES OF DETOXIFICATION The enzymic detoxification of xenobiotics has been classified into two distinct phases which act in a tightly integrated manner. Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

  15. Phase I & II detoxification

  16. THE ROLE OF PHASE I “Phase I is catalysed mainly by the cytochrome P450 system. This family of microsomal proteins is responsible for a range of reactions, of which oxidation appears to be the most important” Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

  17. THE ROLE OF PHASE II “Phase II enzymes catalyse the conjugation of activated xenobiotics to an endogenous water-soluble substrate, such as reduced glutathione (GSH), UDP-glucuronic acid or glycine” Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

  18. Phytonutrients regulate biotransformation “Induction or inhibition of biotransformational enzymes, enzymes that activate or detoxify numerous xenobiotics, is one mechanism by which vegetables may alter cancer risk.” Lampe J. et al. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000; 21(6):1157-62

  19. BIOTRANSFORMATIONAL ENZYMES “Biotransformation enzymes, such as the cytochrome P450 (CYP) isoenzymes, are essential for initiating conversion of lipophilic xenobiotics into more hydrophilic, water-soluble metabolites.” Lampe J. et al. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000; 21(6):1157-62

  20. Functions of Cytochrome P450 Enzymes • The synthesis and degradation of endogenous steroid hormones, vitamins and fatty acid derivatives • Metabolism of drugs, environmental pollutants and carcinogens. Honkakoski P. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 2000;347:321-337

  21. THE IMPORTANCE OF BIOTRANSFORMATION “They (CYP) reduce the half-life of and duration of exposure to xenobiotics and prevent accumulation of the parent compounds.” Lampe J. et al. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000; 21(6):1157-62

  22. Phase 1 Detoxification

  23. Biotransformational enzymes “Cytochrome p450’s support the oxidative, peroxidative and reductive metabolism of such endogenous and xenobiotic substrates as environmental pollutants, agrochemicals, plant allelochemicals, steroids, prostaglandins and fatty acids.” Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002 Dec;3(6):561-97

  24. Biotransformational enzymes “They also display complex sex-, tissue- and development-specific expression patterns which are controlled by hormones or growth factors, suggesting that these CYPs may have critical roles, not only in elimination of endobiotic signalling molecules, but also in their production.” Honkakoski, P. et. al. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J. 2000;347:321-337.

  25. Factors Affecting Phase 1 and Phase 2 Detoxification The two principle phases of biotransformation are susceptible to induction and/or inhibition by two major factors; • Gene polymorphisms leading variable enzyme action and slow and fast metabolisers • Environmental factors – both exogenous and endogenous

  26. Phase 2 Detoxification

  27. Phase II enzymes “The induction of phase II enzymes is considered an important mechanism of protection against chemical stress and carcinogenesis.” Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc. Nat. Acad. Sci. USA. 1990;87:6258-6262

  28. Phase 2 Detoxification Processes • Sulphation • Glucuronidation • Glutathionation • Acetylation • Methylation • Glycination

  29. GSTs ARE THE MAJOR PHASE II ENZYMES “The glutathione transferases (GST’s: also known as glutathione-S-transferases) are major phase II detoxification enzymes found mainly in the cytosol” Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

  30. Glutathione transferase “The primary defence of nature against electrophiles occurs by glutathione transferase (GST) catalysed conjugation to glutathione.” Rinaldi, R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metab Disp. 2002;30:1053-1058

  31. Glutathione transferase The glutathione S-transferases (GST) belong to a group of xenobiotic metabolising phase II enzymes that function as intracellular detoxification systems of mutagens, carcinogens, and other toxic compounds Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Nat Acad Sci 1990;87:6258-6262

  32. GST LEVELS DECREASE PROCARCINOGENS “it is well documented that the proportion of reactive benzo(a)pyrene diol epoxides reacting with DNA in a cellular system is directly related to the amount and nature of glutathione transferases present.” Rinaldi R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metabolism and Disposition 2002;30(10):1053-58

  33. Prevalence of GSTM1 & GSTT1 Polymorphisms The range of GSTM1 & GSTT1 null genotype frequencies range from 40% -50% and from 10%-65% in Western and Asian countries, respectively. Lin J et al. Glutathione S-Transferase M1 and T1 genotypes and endometriosis risk: a case controlled study. Chin Med J 2003;116(5):777-780

  34. GSTM1 & GSTT1 polymorphisms increase environmental disease risk “Both GSTM1 and GSTT1 genetic polymorphisms have been demonstrated to affect susceptibility to various cancers, and may be considered as risk modifiers for various environmentally induced diseases.” Jun, L. et. al. Glutathione-S-transferase M1 and T1 genotypes and endometriosis risk: a case controlled study. Chin Med J 2003;116(5):777-780

  35. PHASE II ENZYME DEFICIENCY IN ENDOMETRIOSIS “We suggest the involvement of both NAT2 (acetylation) and GSTM1 (glutathione conjugation) detoxification system genes in the pathogenesis of endometriosis and the possible impact of NAT2 gene polymorphism in the development of different forms of this disease.” Baranova, H. Possible involvement of arylamine N-acetyltransferase 2, glutathione-s-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod 1999;5(7):636-41

  36. grapefruit

  37. GRAPEFRUIT JUICE DOWNREGULATES CYP3A4 IN THE SMALL INTESTINE “the effect of grapefruit juice on oral felodipine kinetics is its selective down-regulation of CYP3A4 in the small intestine” Lown K et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A4 protein expression. J Clin Invest 1997;99: 2545-53

  38. GRAPEFRUIT JUICE ALTERS DRUG METABOLISM “A single glass of grapefruit juice has been shown to significantly increase the oral availability of a variety of commonly used medications” Lown K et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A4 protein expression. J Clin Invest 1997;99: 2545-53

  39. Hypericum

  40. HYPERICUM ALTERS PHARMACOKINETICS “Recent clinical studies demonstrate the hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin and indinavir.” Moore, L. St. John’s Wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June 20; 97(13):7500-2

  41. HYPERICUM INDUCES CYP3A4 EXPRESSION “Treatment of primary human hepatocytes with hypericum extracts or hyperiforin results in a marked induction of CYP3A4 expression.” Moore, L. St. John’s Wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June 20; 97(13):7500-2

  42. HYPERICUM ALTERS PHARMACOKINETICS “Because CYP3A4 is involved in the oxidative metabolism of 50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John’s wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realised.” Moore, L. St. John’s Wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June 20; 97(13):7500-2

  43. Kava-Kava

  44. Kava-Kava inhibits CYP3A4 activity “extracts of kava-kava contain various inhibitors of CYP3A4 and are likely to cause drug interactions when administered concomitantly with drugs metabolised predominantly by CYP3A4” Unger M, et. al. Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Med. 2002 Dec;68(12):1055-8

  45. Kava-Kava inhibits CYP3A4 activity “Since one case report described the coma of a woman after simultaneous ingestion of kava and alprazolam, a substance known to be metabolised by CYP3A4, an in-vitro-in-vivo correlation is obvious” Unger M, et. al. Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Med. 2002 Dec;68(12):1055-8

  46. Licorice

  47. Liquorice induces CYP activity “While a single liquorice or glycyrrhizin dose was unable to affect the multienzymatic CYP-system, using both schedules of repeated treatment, either liquorice or glycyrrhizin were able to significantly induce hepatic CYP3A- and, to a lesser extent, 2B1- and 1A2-dependent microsomal monooxygenase activities” Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci. 1998; 62(6): 571-82

  48. Liquorice induces CYP activity “These results suggest that the induction of cytochrome P450-dependent activities by the prolonged intake of high liquorice or glycyrrhizin doses, may result in accelerated metabolism of coadministered drugs with important implications for their disposition” Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci 1998; 62(6): 571-82

  49. Echinacea

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