Metabolism of Toxicants

Toxicants Metabolism

• Toxicants (xenobiotics) are catalyzed by enzymes to form metabolites with modified structures.
• Liver is the major site of metabolism, but other sites include plasma, kidney, lung, and gut wall.
• Metabolism can result in:
  • Less toxic chemicals (metabolites)
  • More toxic chemicals (metabolites)
  • Chemicals with different types of effects or toxicity

Sites of Metabolism

• Liver: ideally placed to intercept ingested toxins, has a major role in biotransformation
• Other sites: plasma, kidney, lung, gut wall
• Enzymes occur where needed, e.g. Cytochrome P450 in liver microsomes

The Liver

• Hepatocytes (liver cells) contain microsomes with Cytochrome P450
• Biotransformation occurs in the liver, converting lipophilic toxicants to hydrophilic metabolites

Biotransformation Reactions

• Phase 1 reactions: functionalization of xenobiotics to form reactive groups
  • Hydroxylation
  • Oxidation
  • N-dealkylation
  • Oxidative deamination
• Phase 2 reactions: conjugation of reactive groups with endogenous molecules to form excretable products
  • Conjugations with glucuronic acid, sulphate, acetyl groups, and glutathione

Phase 1 Enzymes

• Cytochrome P450 (CYP): most important enzyme in xenobiotic metabolism, membrane-bound and localized in smooth endoplasmic reticulum
• Flavin-containing monoxygenases (FMO)
• Epoxide hydrolases
• Alcohol/Aldehyde Dehydrogenases
• Monoamine Oxidases
• Xanthine oxidase

Cytochrome P450

• Divided into families, subfamilies, and isoforms (e.g. CYP1, CYP2, CYP3)
• Requires NADPH and O2 for reactions
• Plays a key role in the metabolism of xenobiotics

Factors Affecting Metabolism

• Age: reduced metabolism in aged and children
• Sex: women more sensitive to ethanol
• Species: different metabolism rates among species
• Clinical or physiological conditions: can affect metabolism rates