PHASE II Metabolism:
Conjugation of Phase I metabolite with endogenous substance.
- Most often make very water soluble
- Most often eliminates biological activity
- Energy- and/or energy equivalent-requiring reactions
- Enzyme: UDP glucuronosyl transferase
- Raw substance = Glucose-1-phosphate
- Requires UTP to activate (to UDP-Glucose [UDPG])
- Insects -- glucoside conjugates
- Vertebrates -- UDPG --> UDPGA + NADH
- O-, N-, and S- glycosides common
- Multiple forms (catalytic specificity) produced by alternate splicing at
the UGT 1 locus of at least 7 different forms of exon 1 with remaining, and
constant, region (exons 2-5).
- Activation of sulfur requires ATP (PAPS is conjugate)
- Family of sulfotransferase enzymes
- Sulfonic acid groups added at amine, hydroxyl, or ketone
- Usually less water soluble, but usually less toxic
- S-adenosyl methionine (SAM) most common methyl donor
- Family of methyltransferases form O-, N-, and S- conjugates
- Methylation can activate toxicants (eg., bacterial methylation of metals)
- Replacement of electrophilic substituent with glutathione (SG)
- SG conjugates excretable, but usually converted to mercapturic acid form
(mammals)
Forms of Coenzyme A (CoA) acts as conjugating agent
- acetylation using CoA
-
addition
of group at O, N, or S
- activation using CoA-SH and acylation with endogenous amino
acid
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