Term
| What is biotransformation? |
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Definition
| the metabolic conversion of endogenous and xenobiotic chemicals to more water soluble compounds |
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Term
| When a compound is biotransformed, what changes to the physical properties of a compound are there? |
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Definition
| changes from lipophilicity to hydrophilicity |
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Term
| Are there a lot of enzymes that do biotransformation? |
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Definition
| no - limited number with broad substrate specificities |
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Term
| What types of reactions are involved in phase I and phase II biotransformation? |
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Definition
| I - hydrolysis, reduction, oxidation - expose or introduce functional groups - OH, NH2, SH, COOH * II - glucuronidation, sulfonation, acetylation, methylation, conjugation |
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Term
| What are the results of phase I and phase II reactions? |
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Definition
| I - a small increase in hydrophilicity * II - a large increase in xenobiotic hydrophilicity - this promotes excretion |
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Term
| Where are biotransforming enzymes located? |
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Definition
| widely distributed - most in the liver (microsomes in the ER), but also in skin, lung, kidney, eye, placenta, GI tract |
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Term
| What 2 organs participate in a lot of 1st pass metabolism? |
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Definition
| liver and GI tract (intestinal flora) |
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Term
| What are 2 examples of biotransformations in the liver? |
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Definition
| cyclosporin oxidized by p450, morphine is conjugated with glucuronic acid |
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Term
| Do tissues differ in their ability to biotransform? |
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Definition
| yes - makes a difference in tissue injury |
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Term
| Where is cytochrome p450 located? |
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Definition
| mainly in the phospholipid bilayer in the ER microsomes, in the liver, but the enzymes are found in virtually all tissues |
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Term
| Is cytochrome p450 a phase I or phase II enzyme? |
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Definition
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Term
| What does cytochrome p450 contain and what is special about its physical characteristics? |
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Definition
| it contains heme (iron) and the complex between ferrous cytochrome p450 and CO absorb light maximally at 450nm |
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Term
| What 2 things can p450 do to xenobiotics? |
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Definition
| detoxify them or activate them to toxic or tumorigenic metabolites |
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Term
| What other things does p450 do other than detox/activate xenobiotics? |
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Definition
| catabolism of steroid hormones, bile acids, fat soluble vitamins, and fatty acids |
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Term
| What are the basic reactions that p450 does? |
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Definition
| monooxygenation - it adds 1 atom of oxygen to the substrate and the other gets reduced to water |
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Term
| Does p450 act alone usually? |
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Definition
| no - it usually requires a 2nd enzyme - a flavoprotein |
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Term
| Name 5 types of reactions that are moderated by p450. |
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Definition
| oxidation, hydroxylation, epoxidation, cleavage of esters, dehydrogenation |
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Term
| Give an example of when p450 activates and detoxifies a xenobiotic. |
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Definition
| cyp3A4 activates aflatoxin B1 to hepatotoxic epoxide byt also detoxifies it by hydroxylation to aflatoxin Q1 |
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Term
| What are 3 reasons that there might be decreased p450 activity? |
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Definition
| genetic mutation causing a blockage of synthesis of p450 or an inactive form of the enzyme * exposure to environmental factors * inhibition or inactivation of pre-existing enzyme by a xenobiotic |
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Term
| What are 3 reasons that p450 activity could be increased? |
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Definition
| gene duplication - leads to overexpression of enzymes * environmental factors that induce synthesis of p450 (most common) * stimulation of pre-existing enzyme |
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Term
| What can happen to the biotransformation of a 2nd drug if p450 is inhibited by a 1st drug? |
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Definition
| exaggerated pharmacologic response to the 2nd drug - could make the 2nd drug more toxic |
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Term
| What are 4 major environmental factors that can influence the activity of p450? |
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Definition
| medications, foods, social habits, and disease status |
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Term
| What medications can have an effect on p450? |
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Definition
| barbiturates, anticonvulsants, rifampin |
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Term
| What foods can have an effect on p450? |
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Definition
| charbroiled beef, cruciferous vegetables |
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Term
| Which social habits can affect p450? |
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Definition
| alcohol consumption, cigarette smoking |
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Term
| What are some diseases that can affect the activity of p450? |
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Definition
| diabetes, hyper/hypothyroidism, inflammation, infections |
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Term
| How are knockout mice used to study p450? |
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Definition
| knockout mice are missing various p450 enzymes and you can use them to study the specific role of a particular enzyme in the activation or detox of a xenobiotic |
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Term
| How are studies with knockout mice relevant to humans? |
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Definition
| the counterpart to a knockout mouse can be found in a human counterpart who lacks a certain enzyme - experiments in mice emphasize the importance of genetic variation and disease development |
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Term
| Is methylation a major or minor biotransformation pathway? |
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Definition
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Term
| What does methylation do to a compound? |
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Definition
| decreases water solubility and masks functional groups that might be able to be conjugated by other phase II enzymes |
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Term
| What happens during methylation specifically? |
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Definition
| the methyl group from S-adenosylmethionine is transferred to the substrate by nucleophilic attack on SAM |
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Term
| What are the enzymes that catalyze O-methylation of phenols and catechols? |
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Definition
| phenol-O-methyltransferase - POMT * catechol-O-methyltransferase - COMT |
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Term
| Where are POMT and COMT located? |
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Definition
| POMT is in microsomes, COMT is in cytosol and ER |
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Term
| How is COMT made, gene-wise? |
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Definition
| 1 gene, 2 transcription sites - 1 will give COMT in the cytosol, the other gives COMT in the ER |
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Term
| What are some substrates for COMT? |
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Definition
| epinephrine, norepinephrine, catecholamine neurotransmitters, and catechol drugs like L-dopa |
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Term
| What are the 2 main carboxylesterases? |
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Definition
| cholinesterase and organophophatases |
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Term
| What are carboxylesterases? Where are they located? |
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Definition
| glycoproteins that are present in a wide variety of tissues, including serum - most active in the liver |
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Term
| What to carboxylesterases do to drugs? Give a specific example. |
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Definition
| generate active metabolites from amide or ester prodrugs, important in activation of anticancer drugs - i.e.lovastatin-->lovastatin-B-hydroxyl acid, which inhibits HMG-CoA reductase which lowers cholesteral |
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Term
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Definition
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Term
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Definition
| liver, kidneys, lung, and gastric mucosa |
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Term
| What are the 4 types of ADH and what do they metabolize? |
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Definition
| I - ethanol oxidation * II - oxidation of larger aromatic alcohols * III - formaldehyde * IV - oxidizes retinol, ethanol |
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Term
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Definition
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Term
| Where is ADH II found? III? IV? |
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Definition
| II - liver mainly * III - all tissues * IV - stomach, not in liver |
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Term
| Why is ADH IV interesting? |
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Definition
| b/c it oxidizes retinol, which is required for epithelial growth and differentiation and it may be inhibited by alcohol consumption |
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Term
| What specifically does ADH metabolize ethanol to? |
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Definition
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Term
| Why does drinking on an empty stomach make you drunk quicker? |
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Definition
| gastric ADH activity decreases when you fast |
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Term
| What is the major pathway of xenobiotic biotransformation in mammals? |
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Definition
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Term
| What does glucuronidation require? |
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Definition
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Term
| Where are glucuronidation enzymes found? |
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Definition
| in the ER of the liver, intestine, skin, and kidneys |
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Term
| What are characteristics of glucuronide conjugates? How are they excreted? |
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Definition
| very water soluble and polar * urine and bile |
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Term
| What are glucuronides of xenobiotics substrates for? |
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Definition
| b-glucuronidase that's in intestinal flora |
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Term
| What is the cofactor for glucuronidation? |
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Definition
| uridine diphosphate glucuronic acid |
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Term
| What are Crigler-Najjar and Gilbert's diseases caused by? What is particularly hepatotoxic to these people? |
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Definition
| defects in bilirubin conjugation - bilirubin conjugating enzyme UGT1A1, which normally glucuronidates acetaminophen, which is why this is hepatotoxic to them |
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Term
| What is sulfonation catalyzed by? What does this process produce? |
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Definition
| sulfotransferases * highly water-soluble sulfuric acid |
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Term
| How are sulfate conjugates excreted? |
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Definition
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Term
| How is sulfonation good and bad? |
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Definition
| good b/c it can decrease the pharmaco-and toxicologic activity of xenobiotics, but bad b/c it has a role in activating aromatic amines and PAH to tumorigenic metabolites |
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Term
| What is the major route of biotransformation for xenobiotics that have an aromatic amine or hydrazine group? |
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Definition
| acetylation and glutathione |
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Term
| Why are electrophiles bad? |
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Definition
| they can bind to nucleophiles like proteins and nucleic acids and cause cellular damage and genetic mutation |
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Term
| What is glutathione a cofactor for? What does it help protect cells against? |
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Definition
| glutathione peroxidase * lipid peroxidation |
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