Xenobiotic Metabolism (Miller)
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| Lecture 56 | Xenobiotic Metabolism
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| Strategy to excrete xenobiotics is to increase ___. | solublity
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| Solubility can be increased by: | functionalization, conjugation, and transport
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| Functionalization | Introduce or expose polar group, create a nucleophile, and oxidation and bond cleavage
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| Conjugation | Couple polar group, nucleophile-electrophile reaction
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| Transport | Alter the localization
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| Cytochrome P450 | Membrane-bound heme (Fe) protein complex
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| Lipophilic substrates of P450 include: | endobiotic and xenobiotic
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| Endobiotic examples: | steroids and arachidonic acid
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| Xenobitiotic examples: | food additives, environmental pollutants, and drugs
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| P450 metabolizes >___% of drugs. | >50%
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| P450 main site of action is in the ___. | liver
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| P450 has ___ substrate specificity. | overlapping (i.e. low specificity)
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| Diazepam has ___ metabolic pathways leading to common end product. | multiple
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| CYP2C19 | N-demethylation
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| CYP3A34 | Ring hydroxylation
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| Xenobiotic metabolism is not an ___ process. | efficient
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| Seldane/Terfenadine | Antihistamine, one toxic product & one metabolically active product, caused cardiac arrhythmias/blackouts/deaths, Allegra is improved design
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| Benzo[a]pyrene has a toxic ___ form. | epoxide (electrophile)
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| The epoxide form ___ DNA. | modifies (at the nitrogen bases)
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| Flavin Monooxygenase (FMO) is ___ bound. | membrane bound (microsomal)
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| FMO contains ___, not heme. | flavin
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| FMO catalytic reactions: | oxidation of nitrogen, phosphorous, and sulfur (similar to P450)
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| N-oxidation of nicotine produces ___. | nicotine N-oxide (inactive)
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| S-oxidation of cimetidine/Tagamet produces ___. | cimetidine S-oxide (inactive)
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| Tagamet is used to treat: | (blocks acid secretion from the stomach) ulcers, gastro-esophageal disorder (GERD), and excessive acid secretion
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| Alcohol Dehydrogenase (ADH) | Cytosolic, parenchymal liver cells, converts alcohols to aldehydes
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| Pyrazole | Inhibits ADH
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| Aldehyde Dehydrogenase (ALDH) | Mitochondrial, cytosolic, and microsomal forms, primarily in the liver, oxidizes aldehydes to acids
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| Disulfiram | Inhibits ALDH
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| ALDH has ___ substrate specificity, | broad
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| UDP-glucuronosyl transferase (UGT) coupling group | glucuronic acid
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| Sulfotransferase (SULT) coupling group: | sulfate
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| Glutathione-S-transferase (GST) coupling group: | glutathione
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| N-acetyltransferase (NAT1/NAT2) coupling group: | acetic acid
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| ___ is the major route of conjugative metabolism in most mammals. | Glucuronidation
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| Glucuronidation is catalyzed by ___. | UGT
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| UGT is ___ bound, localized in the ___. | membrane bound, ER
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| Glucuronidation products: | O-glucuronides -COOH, N-glucuronides –NH2, S-glucuronides –SH
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| Conjugation requires ___ group. | nucleophilic
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| SULT | Second most important conjugative enzyme, soluble, non-inducible
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| SULT substrates: | steroids, hormones, xenobiotics
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| Cofactor for SULT: | PAPS (activated electrophile), rate limiting
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| GST catalyzes: | glutathione conjugation
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| GST substrates: | steroids, hormone, and few xenobiotics (anticancer)
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| GST requires ___ cofactor. | glutathione
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| Glutathione in GST serves as the: | intracellular reducing agent, non-catalyzed trap for electrophiles, and amino acid tansporter
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| GST forms highly water-soluble ___ acids. | mercaptouric
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| N-acetyl transferase catalyzes: | acetylation
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| NAT’s polymorphic isoforms are: | NAT1 and NAT2
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| NAT1 is in the ___, and NAT2 ___. | liver, colon/other tissues
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| NAT isoforms catalyze the same reaction but have different: | substrate specificity
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| NAT causes the transfer of an acetyl group, which causes the molecule to: | become more polar, but not have a charge
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| ATP Binding Cassette (ABC) transporter, utilizes ___ to transport. | ATP
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| 95% of acetaminophen is broken down to nontoxic metabolites ___ and ___. | SULT (65%) and UGT (35%)
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| <5% of acetaminophen metabolism produces toxic ___, catalyzed by ___. | NAPQI, CYP2E1
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| NAPQI causes: | cell death and consumption of GSH (regeneration)
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| Alcohol consumption induces ___, increasing synthesis of NAPQI. | CYP2E1
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