Biochemistry: Xenobiotic Metabolism

Xenobiotics

• 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.

Metabolism of Xenobiotics

• Xenobiotics are metabolized in two phases: Phase I and Phase II.

Phase I

• 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

• 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.

Phase II

• 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.

Toxic Effects of Xenobiotics

• 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.