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