Phase I Reactions in Xenobiotic Metabolism

Study Notes

Phase I Reactions

Also known as hydroxylation reactions, introducing or exposing a functional group for sequential conjugation in phase II reactions.
Mainly catalyzed by monooxygenases, mixed function oxidases, or cytochrome P450s.
Other important enzymes include Aldehyde and alcohol dehydrogenase, Deaminases, Esterases, Amidases, and Epoxide hydrolases.

Oxidation

Most foreign substances are detoxified by oxidation.
Includes the oxidation of alcohols, aldehydes, amines, aromatic hydrocarbons, and sulfur compounds.
Aliphatic compounds are more easily oxidized than aromatic ones.

Oxidation of Alcohols

Both aromatic and aliphatic alcohols undergo oxidation to form their corresponding acids.
Examples: Methanol → formaldehyde → formic acid, Ethanol → Acetaldehyde → acetic acid, Benzyl alcohol → Benz aldehyde → benzoic acid.

Methanol Toxicity

Methanol has relatively low toxicity and is metabolized in the liver.
In the first step of degradation, methanol is transformed to formaldehyde via enzyme ADH.
Transformation of formaldehyde to formic acid via aldehyde dehydrogenase is faster.
The metabolism of formic acid is very slow, leading to accumulation in the body, which results in metabolic acidosis.
The major damage occurs to the optic nerve.
Ethanol is given as an antidote, since it is the substrate of ADH, methanol is spared.

Oxidation of Aldehydes

Aldehydes are oxidized to corresponding acids.
Acid thus formed is further conjugated in phase II, e.g., Benz aldehyde → benzoic acid, which is conjugated with glycine to form Hippuric acid.

Oxidation of Aromatic Hydrocarbons

Aromatic hydrocarbons are oxidized to phenolic compounds.
Which can further conjugated with glucuronic acid or sulphuric acid in phase II reactions.

Oxidation of Amines

Many primary aliphatic amines undergo oxidation to form the corresponding acids and nitrogen is converted to urea.
Examples: Benzyl amine → Benzoic acid + urea.

Oxidation of Anilids and Sulphur Containing Compounds

Anilids are oxidized to corresponding phenols.
Acetanilide is oxidized in the body to form P-acetyl amino phenol.
Sulphur compounds: Organic sulfur is oxidized to sulfuric acid.

Cytochrome P450

Most of the oxidation reactions of detoxification are catalysed by monooxygenase (or) cytochrome P450.
Also known as mixed function oxidases, associated with the microsomes of the liver.
Properties: hemoproteins, exhibit broad substrate specificity, versatile catalysts, located in smooth ER, NADPH dependent enzymes, inducible enzymes.

Reduction

Reduction is less common and less important than oxidation in human beings.
Examples: Picric acid → Picramic acid, Chloral hydrate → Trichloroethanol.

Hydroxylation

Detoxification of a number of drugs and steroids occur by hydroxylation.
These reactions are catalyzed by cytochrome P450 dependent monooxygenases.
Examples: Pentobarbital → Hydroxy phenobarbital, Meprobamate → P-OH meprobamate.

Hydrolysis

Certain therapeutic compounds undergo hydrolysis.
Hydrolysis of the bond such as ester, glycoside, and amide is important in the metabolism of xenobiotics.
Examples: Nicotinamide, p-methyl amino azobenzene, P-dimethyl amino benzene, estrogen, Catecholamine, etc.

Methylation

Reactions: transmethylation, S-adenosyl methionine as the methyl donor.
Examples: Nicotinamide → N-Methyl Nicotinamide, p-Methyl amino azobenzene → P-Dimethyl amino azobenzene.

Conjugation with Amino Acids

Compounds conjugated with glycine: benzoic acid, phenyl acetic acid, cholic acid, and deoxy cholic acid.
Examples: Benzyl coA + Glycine → Hippuric acid, Phenyl acetic acid + Glycine → Phenyl aceturic acid.

Conjugation with Glutathione

Glutathione is a tripeptide consisting of Glutamic acid, cysteine, and glycine.
Organic compounds such as alkyl or aryl halides, alkenes, nitro compounds, and epoxides get conjugated with cysteine of glutathione.
Results in the formation of mercapturic acid.

Detoxification by Drugs

Some drugs are administered to detoxify foreign substances.
Examples: BAL (British Anti Lewisite) to overcome the toxic effects of certain heavy metals such as arsenic, mercury, and cadmium.

Description

Learn about the process of phase I reactions in xenobiotic metabolism, which involves hydroxylation reactions and the activation of functional groups for phase II reactions. Explore the key enzymes involved in phase I reactions such as monooxygenases, cytochrome P450s, and dehydrogenases.