Biochemistry: Xenobiotic Metabolism

Study Notes

Xenobiotics are chemical compounds foreign to the body, including drugs, food additives, and environmental pollutants, as well as naturally occurring compounds in plant foods.
Most xenobiotics are metabolized, mainly in the liver, in a process known as biotransformation.

The major reaction of Phase I is hydroxylation catalyzed by a variety of monooxygenases, known as the cytochromes P450.
Phase I reactions are broadly grouped into three categories: oxidation, reduction, and hydrolysis.
Cytochrome P450 is a heme enzyme that plays a crucial role in Phase I reactions.
At least half of the common drugs that we ingest are metabolized by isoforms of cytochrome P450.

Cytochrome P450 is a superfamily of enzymes that catalyze the oxidation of many xenobiotics.
There are at least 57 genes encoding cytochrome P450 in the human genome.
Cytochromes P450 are generally located in the endoplasmic reticulum of cells, especially in the liver.
Many cytochromes P450 are inducible, which has important implications for drug interactions.

In Phase II, the hydroxylated species are conjugated with a variety of hydrophilic compounds such as glucuronic acid, sulfate, or glutathione.
Types of Phase II reactions include glucuronidation, conjugation with amino acids, conjugation with glutathione, sulfation, acetylation, and methylation.
Glutathione (G-SH) is important in the phase II metabolism of electrophilic compounds, forming glutathione S-conjugates that are excreted in urine and bile.

Responses to xenobiotics can include toxic, immunological, and carcinogenic effects.
Covalent binding of xenobiotics or their metabolites to macromolecules, including DNA, RNA, and protein, can lead to cell injury (cytotoxicity) and even cell death.
Reactive metabolites of xenobiotics can bind to proteins, acting as haptens, and altering their antigenicity, potentially initiating autoimmune disease.
Reactions of some activated xenobiotics with DNA are important in chemical carcinogenesis.