OXIDATION, REDUCTION, HYDROLYSIS

Aromatic Hydroxylation

Refers to the mixed-function oxidation of aromatic compounds (arenes) to their corresponding phenolic metabolites (arenols).

Phenyl Groups

In humans, aromatic hydroxylation is a major route of metabolism for many drugs containing?

O- glucuronide conjugate

The major urinary metabolite of phenytoin found in humans is the?

- Rearrangement to Arenols
- React with Water to form trans-Dihydrodiols
- Neutralize with Glutathione

To prevent the binding of arene oxide to macromolecules:

Rearrangement to Arenols

Quantitatively, the most important detoxification reaction for arene oxides is the spontaneous?

Epoxide Hydrase

Hydration (i.e., nucleophilic attack of water on the epoxide) of arene oxides to yield inactive trans-dihydrodiol metabolites. This reaction is catalyzed by microsomal enzymes called?

- Cyclohexene Oxide
- 1,1,1- Trichloropropene-2,3,-oxide

Often epoxide hydrase inhibitors such as:

Ames

Epoxide hydrase inhibitors are used for, what test? (A test for mutagenicity; how cancerous)

GSH S- transferases

Another mechanism to neutralize the toxic effect of arene oxide:
A second enzymatic reaction involves nucleophilic ring opening of the arene oxide by the sulfhydryl (-SH) group present in GSH to yield the corresponding GSH adduct. The reaction is catalyzed by various

Epoxides

OLEFINS
The metabolic oxidation of olefinic carbon–carbon double bonds leads to the corresponding? (tend to be somewhat more stable than the arene oxides formed from aromatic compounds)

Alcofenac

OLEFINS
- Metabolized to dihydroxy alcofenac
- The epoxide metabolite from which it is derived, is present in minute amounts.

Primary Alcohol

BENZYLIC CARBON
Are often oxidized further to aldehydes and carboxylic acids (CH2OH → CHO → COOH)

Benzylic Carbons

Carbon atoms attached to aromatic rings are susceptible to oxidation, thereby forming the corresponding alcohol metabolite.

Secondary Alcohol

BENZYLIC CARBON
Are converted to ketones by soluble alcohol and aldehyde dehydrogenases.

Tolbutamide

Example of Benzylic Carbon Oxidation

w- oxidation

Metabolic oxidation at the terminal methyl group often is?

w-1 oxidation

Oxidation of the penultimate carbon atom is called?

Diazepam

Example of a-carbons in Carbonyl and Imines Oxidation
- Oxidized to its 3-hydroxy metabolite
The C-3 carbon atom undergoing hydroxylation is a (alpha) to both a lactam carbonyl and an imino functionality

Alpha- Carbon

What carbon is directly next to a specific functional group?

Valproic Acid

Example of Aliphatic and Alicyclic Carbons Oxidation

Hepatic CYP mixed-function oxidase enzymes

The oxidative removal of alkyl groups (particularly methyl groups) from tertiary aliphatic and alicyclic amines is carried out by?

Imipramine

Example of Tertiary and Alicyclic Amines
- Monodemethylated to desmethylimipramine (desipramine)
- This major plasma metabolite is pharmacologically active in humans and contributes substantially to the antidepressant activity of the parent drug

lactam

Alicyclic tertiary amines often generate _____ metabolites by a-carbon hydroxylation reactions.

Nicotine

Example of Alicyclic tertiary amines often generate lactam metabolites by a-carbon hydroxylation reactions.
- Hydroxylated initially at the ring carbon atom a to the nitrogen to yield a carbinolamine intermediate
- Furthermore, enzymatic oxidation of this cyclic carbinolamine generates the lactam metabolite continine

Secondary Amines

Are susceptible to oxidative N-dealkylation, oxidative deamination, and N-oxidation reactions.

Carbinolamine

N-dealkylation of secondary amines proceeds by the ________ pathway.

Primary Amine Metabolite

Dealkylation of secondary amines gives rise to the corresponding?

Propranolol

Example of Secondary or Primary Amines Oxidation
- Undergoes N-deisopropylation to form a primary amine

T

T or F
If a-carbon hydroxylation cannot occur, then oxidative deamination is not possible.

Phenmetrazine

Some secondary alicyclic amines, like their tertiary amine analogs, are metabolized to their corresponding lactam derivatives.

Example: