Phase I - Functionalization of compounds

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Summation

Phase 1 of metabolism is concerned with functionalization, that is the introduction or exposure of functional groups on the chemical structure of a compound. This provides a 'handle' for phase 2 conjugating species with which to react with. Many xenobiotics are lipophilic and almost chemically inert (e.g. PAHs) so would not necessarily undergo a phase 2 reaction. Making them more chemically reactive would facilitate their excretion but also increases their chance of reacting with cellular macromolecules (e.g. proteins, DNA). There is a fine balance between producing a more reactive metabolite and conjugation reactions.
There are two groups of enzymes in phase 1 - oxidoreductases and hydrolases. Oxidoreductases introduce an oxygen atom into or remove electrons from their substrates. The major oxidoreductase enzyme system is called the P450 monooxygenases. Other systems include flavin-containing monooxygenases (FMO), cyclooxygenases (COX) and monoamine oxidases (MAO). Hydrolases hydrolyse esters, amides, epoxides and glucuronides.

Literature References
PubMed ID Title Journal Year
17125408 Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics

Strolin Benedetti, M, Whomsley, R, Baltes, E

Expert Opin Drug Metab Toxicol 2006
12369887 The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans

Danielson, PB

Curr Drug Metab 2002
16584116 Cytochrome P450s and other enzymes in drug metabolism and toxicity

Guengerich, FP

AAPS J 2006
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