Metabolism of Xenobiotics

Toxication and Detoxication: Must consider both parent and metabolites:

Metabolism may either decrease or increase toxicity.Toxicants can be formed in a variety of ways:

A) Parent compound toxic. Metabolites non-toxic.

B) Parent compound non-toxic. Metabolites toxic.

• Toxic metabolites formed in situ

  

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• Toxic metabolites formed in liver and transported
  • e.g., Parathion (nerve poison):

  

ABSORPTION/ELIMINATION:

1. CHARACTERISTICS OF XENOBIOTICS?

• Lipophilic
• Penetrate membranes by diffusion
• Transported by lipoproteins in blood

1. HOW ELIMINATE?

• Diffusion (limitations?)
• Excrete (limitations?)
• MAKE IT WATER SOLUBLE!!!!!!

Xenobiotic metabolism consists of two phases:

1. Phase I -- Polar reactive groups introduced
2. Phase II -- Covalent "conjugation" to endogenous substances:

• sugars
• amino acids
• inorganic ions

Generalizations

1. Changes activity of xenobiotics

• Quantitative (detox or activation)
• Qualitative (disposition and effect)

2. Phase I products most often more polar and less lipophilic

3. Phase II reactions most often abolish biological activity and add to polarity

4. Biotransformation requires energy or energy equivalents

5. Enzyme systems are inducible

6. Enzyme systems are saturable, frequently by depletions of cofactors

7. Systems are age, gender, and species dependent and are affected by exgogenous environmental factors

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