Lecture 2
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Explain the classifications of P-450 inhibition
-reversible inhibition -metabolic intermediate complexation inhibition -irreversible inhibition
name some things that present REVERSIBLE p450 inhibition
nitrogen heterocycles imidazole functional group for example, which is contained in antifungal drug classes. (go back to this and go over nitrogen heterocycles. azo?)
give an example of irreversible p450 inhibition
-heme alkylation -covalent binding of apoprotein the inhibitor can target either the CATALYTIC or the APOPROTEIN site
Give an example of metabolic intermediate complexation inhibition
alkylamines such as SKS-525A initial binding and At least 1 cycle of metabolic reactions occurs – an intermediate is produced which is then inhibited by an alkylamine (SKF-525A)
what is a standard drug for testing the inhibition of cytochrome p450 in vitro drug metabolism studies?
SKF-525A (an alkylamine)
name the 3 phase 1 reactions
oxidations reductions hydrolyses
name 4 compounds that undergo phase 1 reduction reactions
• aromatic and heteroaromatic nitrogen compounds • aromatic azo compounds (N=N) • Aromatic sulfoxides (S=O) • carbonyl groups (ketones and aldehydes)
name 5 compounds that undergo phase 1 hydrolysis reactions
• carboxylic esters • organic phosphate esters • organic sulfate esters • organic nitrite and nitrate esters • amides
what 3 compounds undergo oxidative desulfurization? is this phase 1 or phase 2?
phase 1 thioketones thioamides thiophosphates
what is the issue with drugs that undergo oxidative desulfurization?
toxic sulfur is produced from these reactions (SO42-)
true or false in the oxidation of primary alcohols, once carboxylic acid is reached no further oxidation is possible
true
what happens when a secondary alcohol is oxidized? what enzyme catalyzes this? is it reversible or irreversible? is further oxidation possible?
a KETONE is formed ADH (alcohol dehydrogenase) catalyzes. it is REVERSIBLE NO FURTHER OXIDATION IS POSSIBLE
TRUE OR FALSE the oxidation of alcohols is not catalyzed by the p450 system
TRUE
explain why the oxidation of a primary alcohol to an aldehyde is reversible, but the oxidation of an aldehyde to carboxylic acid is irreversible
ADH (alcohol dehydrogenase) catalyzes the oxidation of a primary alcohol to an aldehyde. this enzyme is found everywhere (bulk in cytosol) and is therefore very plentiful ALDH (aldehyde dehydrogenase) catalyzes the oxidation of aldehyde to carboxylic acid. the highest capacity of this enzyme is in the mitochondria, and is thus not as plentiful.
explain the difference and similarities between the oxidation of methanol vs ethanol
both are primary alcohols. our body can’t tolerate methanol as much as ethanol. Methanol will be oxidized to carboxylic acid (formic acid). this can cause acidosis and the buildup of aldehyde (intermediate - formaldehyde) can cause blindness ethanol is first oxidized to acetaldehyde, and then acetic acid. acetic acid reacts with coenzyme A to give acetyl coA which participates greatly in lipid and carbohydrate metabolism.
What is the coenzyme in the oxidation of alcohols? is it involved in both steps? (in the case of primary alcohols)
NADH involved in both steps NAD+ reduced to NADH
give the scenarios in which alkyl side chains can be oxidized
-terminal carbon oxidation -w-1 carbon oxidation
explain the product of terminal carbon oxidation
a primary alcohol is produced. this has 2 potential fates. can be: -oxidized further via ADH and ALDH to aldehyde and then carboxylic acid -can stay as alcohol and undergo conjugation (ie: glucuronidation)
explain the product of w-1 carbon oxidation
a secondary alcohol is produced. this can be oxidized further to ketone via ADH OR can remain as alcohol and undergo conjugation (since it has a polar functional group)
what is the allylic position?
the allylic carbon is the carbon attached to another carbon that is part of a C=C double bond
oxidative deamination is mechanistically identical to what other reaction?
n-dealkylation
explain the compounds that are able to undergo oxidative deamination
• primary amines on primary carbon atoms • primary amines on secondary carbon atom
Explain the mechanism of oxidative deamination of primary amines on primary carbon atom
the molecule is oxidized to its corresponding alcohol. this forms CARBINOLAMINE which is chemically unstable metabolite and falls apart. Since amine is a good leaving group, it comes off when =O is formed. this forms…. ALDEHYDE +NH3 (ammonia) keep in mind, this aldehyde can be oxidized further to its carboxylic acid or reduced back to its alcohol
Explain the concern with big molecules in terms of metabolism
many metabolic reactions are possible on a big molecule, but not all will occur. we want to know all the metabolic reactions possible on a molecule. Some are more likely to happen than others