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Detoxification of xenobiotics ppt BIOCHEMISTRY vkunder637@gmail.com
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Detoxification of xenobiotics ppt BIOCHEMISTRY vkunder637@gmail.com

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  • In addition to nutrients, our diet also contains a large number of chemicals called xenobiotics, which have no nutritional value, are of no use in the body, and can be harmful if consumed in excessive amounts. These compounds occur naturally in foods, can enter the food chain as contaminants, or can be deliberately introduced as food additives.
  • Hydroxylation is the chief reaction involved in phase1. The responsible enzymes are called monooxygenasesor cytochrome P450s; the human genome encodes atleast 14 families of these enzymes. Estimates of thenumber of distinct cytochrome P450s in human tissuesrange from approximately 35 to 60. The reaction catalyzedby a monooxygenase (cytochrome P450) is asfollows: RH above can represent a very wide variety of xenobiotics,including drugs, carcinogens, pesticides, petroleumproducts, and pollutants (such as a mixture ofPCBs). In addition, endogenous compounds, such ascertain steroids, eicosanoids, fatty acids, and retinoids,are also substrates. The substrates are generally lipophilicand are rendered more hydrophilic by hydroxylation.Table 53–1. Some properties of humancytochrome P450s.• Involved in phase I of the metabolism of innumerablexenobiotics, including perhaps 50% of the drugs administeredto humans• Involved in the metabolism of many endogenous compounds(eg, steroids)• All are hemoproteins• Often exhibit broad substrate specificity, thus acting onmany compounds; consequently, different P450s may catalyzeformation of the same product• Extremely versatile catalysts, perhaps catalyzing about 60types of reactions• However, basically they catalyze reactions involving introductionof one atom of oxygen into the substrate and oneinto water• Their hydroxylated products are more water-soluble thantheir generally lipophilic substrates, facilitating excretion• Liver contains highest amounts, but found in most if notall tissues, including small intestine, brain, and lung• Located in the smooth endoplasmic reticulum or in mitochondria(steroidogenic hormones)• In some cases, their products are mutagenic or carcinogenic• Many have a molecular mass of about 55 kDa• Many are inducible, resulting in one cause of drug interactions• Many are inhibited by various drugs or their metabolicproducts, providing another cause of drug interactions• Some exhibit genetic polymorphisms, which can result inatypical drug metabolism• Their activities may be altered in diseased tissues (eg, cirrhosis),affecting drug metabolism• Genotyping the P450 profile of patients (eg, to detectpolymorphisms) may in the future permit individualizationof drug therapy
  • Hydroxylation is the chief reaction involved in phase1. The responsible enzymes are called monooxygenasesor cytochrome P450s; the human genome encodes atleast 14 families of these enzymes. Estimates of thenumber of distinct cytochrome P450s in human tissuesrange from approximately 35 to 60. The reaction catalyzedby a monooxygenase (cytochrome P450) is asfollows: RH above can represent a very wide variety of xenobiotics,including drugs, carcinogens, pesticides, petroleumproducts, and pollutants (such as a mixture ofPCBs). In addition, endogenous compounds, such ascertain steroids, eicosanoids, fatty acids, and retinoids,are also substrates. The substrates are generally lipophilicand are rendered more hydrophilic by hydroxylation.Table 53–1. Some properties of humancytochrome P450s.• Involved in phase I of the metabolism of innumerablexenobiotics, including perhaps 50% of the drugs administeredto humans• Involved in the metabolism of many endogenous compounds(eg, steroids)• All are hemoproteins• Often exhibit broad substrate specificity, thus acting onmany compounds; consequently, different P450s may catalyzeformation of the same product• Extremely versatile catalysts, perhaps catalyzing about 60types of reactions• However, basically they catalyze reactions involving introductionof one atom of oxygen into the substrate and oneinto water• Their hydroxylated products are more water-soluble thantheir generally lipophilic substrates, facilitating excretion• Liver contains highest amounts, but found in most if notall tissues, including small intestine, brain, and lung• Located in the smooth endoplasmic reticulum or in mitochondria(steroidogenic hormones)• In some cases, their products are mutagenic or carcinogenic• Many have a molecular mass of about 55 kDa• Many are inducible, resulting in one cause of drug interactions• Many are inhibited by various drugs or their metabolicproducts, providing another cause of drug interactions• Some exhibit genetic polymorphisms, which can result inatypical drug metabolism• Their activities may be altered in diseased tissues (eg, cirrhosis),affecting drug metabolism• Genotyping the P450 profile of patients (eg, to detectpolymorphisms) may in the future permit individualizationof drug therapy
  • Fig. 30.3. Metabolic routes of UDP-glucuronate. UDP-glucuronate is formed from UDPglucose(shown in black). Glucuronate from UDP-glucuronate is incorporated into glycosaminoglycans,where certain of the glucuronate residues are converted to iduronate (seeChapter 49). UDP-glucuronate is a precursor of UDP-xylose, another sugar residue incorporatedinto glycosaminoglycans. Glucuronate is also transferred to the carboxyl groups ofbilirubin or the alcohol groups of steroids, drugs, and xenobiotics to form glucuronides. The“ide” in the name glucuronide denotes that these compounds are glycosides. Xenobiotics arepharmacologically, endocrinologically, or toxicologically active substances not endogenouslyproduced and therefore foreign to an organism. Drugs are an example of a xenobiotic. The function of glucuronate in the excretion of bilirubin, drugs, xenobiotics, andother compounds containing a hydroxyl group is to add negative charges andincrease their solubility.
  • Fig. 30.3. Metabolic routes of UDP-glucuronate. UDP-glucuronate is formed from UDPglucose(shown in black). Glucuronate from UDP-glucuronate is incorporated into glycosaminoglycans,where certain of the glucuronate residues are converted to iduronate (seeChapter 49). UDP-glucuronate is a precursor of UDP-xylose, another sugar residue incorporatedinto glycosaminoglycans. Glucuronate is also transferred to the carboxyl groups ofbilirubin or the alcohol groups of steroids, drugs, and xenobiotics to form glucuronides. The“ide” in the name glucuronide denotes that these compounds are glycosides. Xenobiotics arepharmacologically, endocrinologically, or toxicologically active substances not endogenouslyproduced and therefore foreign to an organism. Drugs are an example of a xenobiotic. The function of glucuronate in the excretion of bilirubin, drugs, xenobiotics, andother compounds containing a hydroxyl group is to add negative charges andincrease their solubility.
  • Fig. 30.3. Metabolic routes of UDP-glucuronate. UDP-glucuronate is formed from UDPglucose(shown in black). Glucuronate from UDP-glucuronate is incorporated into glycosaminoglycans,where certain of the glucuronate residues are converted to iduronate (seeChapter 49). UDP-glucuronate is a precursor of UDP-xylose, another sugar residue incorporatedinto glycosaminoglycans. Glucuronate is also transferred to the carboxyl groups ofbilirubin or the alcohol groups of steroids, drugs, and xenobiotics to form glucuronides. The“ide” in the name glucuronide denotes that these compounds are glycosides. Xenobiotics arepharmacologically, endocrinologically, or toxicologically active substances not endogenouslyproduced and therefore foreign to an organism. Drugs are an example of a xenobiotic. The function of glucuronate in the excretion of bilirubin, drugs, xenobiotics, andother compounds containing a hydroxyl group is to add negative charges andincrease their solubility.
  • Transcript

    • 1. • Detoxification pathways and waste disposal pathways are metabolic pathways devoted to removing toxins that can be present in our diets or in the air we breathe, introduced into our bodies as drugs, or generated internally from the metabolism of dietary components.
    • 2. • Food additives, poisons, toxins, certain drugs, chemicals, environmental pollutants, pesticides and other foreign substances.
    • 3. Phases of Detoxification Processes Phase I Phase II
    • 4. Oxidation Alcohol Aldehydes Amines Aromatic hydrocarbons Sulfur compounds Drugs Ethanol → Acetic acid Methanol → Formic acid Benzaldehyde → Benzoic acid Aliphatic amine → Aliphatic acid + Urea
    • 5. Oxidation Many reactions of cytochrome P450 involve the addition of a hydroxyl group to xenobiotics Hydroxylation
    • 6. Hydroxylation The responsible enzymes are called monooxygen ases or cytochrome P450
    • 7. Cytochrome P450
    • 8. NADPH +H+ NADP+ NADPH –Cyt P450 reductase NADPH –Cyt P450 reductase Cyt P450 Cyt P450 XH X-OH oxidised oxidisedreduced reduced
    • 9. Cytochrome P450 Multiple forms Hemoproteins Microsomes of liver NADPH dependant Phosphatidyl choline Inducible enzyme
    • 10. Hydroxylation
    • 11. Reduction
    • 12. Hydrolysis
    • 13. Conjugation Glucuronic acid Glutathione Sulfate Glycine Cysteine Acetate Glutamine Conjugation means the chemical combination of one compound with another compound.
    • 14. Conjugation with Glucuronic acid
    • 15. Conjugation with Glucuronic acid Benzoic acid + → Benzoyl glucuronide + UDP Paracetamol + → Conjugated product + UDP Diclofenac sodium + → Conjugated product + UDP
    • 16. Conjugation with Glycine
    • 17. Conjugation with Glutathione
    • 18. X-R + GSH X-S-G S-X-Cysteinylglycine S-X-Cysteine Mercapturic acid RH Glutamine Glycine Acetyl-CoA CoA-SH Conjugation reaction by glutathione
    • 19. Conjugation with Glutatmine Phenylacetate Phenylacetyl glutamine Glutamine
    • 20. Conjugation with sulfate

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