Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions

B Testa, University Hospital Centre, Lausanne, Switzerland © 2007 Elsevier Ltd. All Rights Reserved.

5.06.1 Introduction 133

5.06.2 Reactions of Hydrolysis and Hydration 134

5.06.2.1 Hydrolases 134

5.06.2.2 Substrates of Hydrolases 135

5.06.2.2.1 Esters 135

5.06.2.2.2 Amides 138

5.06.2.2.3 Peptides 139

5.06.2.3 Epoxide Hydrolases and Their Reactions 140

5.06.2.3.1 Epoxide hydrolases 140

5.06.2.3.2 Arene oxide substrates 141

5.06.2.3.3 Alkene oxide substrates 142

5.06.3 Reactions of Conjugation 144

5.06.3.1 Criteria of Conjugation 145

5.06.3.2 Reactions of Methylation 145

5.06.3.2.1 Mechanism and multiplicity of methyltransferases 145

5.06.3.2.2 Substrates of methyltransferases 146

5.06.3.3 Formation of Sulfate and Phosphate Conjugates 147

5.06.3.3.1 Mechanism and multiplicity of sulfotransferases 147

5.06.3.3.2 Substrates of sulfotransferases 148

5.06.3.3.3 Formation of phosphate conjugates 149

5.06.3.4 Conjugations with Glucuronic Acid 150

5.06.3.4.1 Mechanism and multiplicity of UDP-glucuronyltransferases 150

5.06.3.4.2 Substrates of UDP-glucuronyltransferases 150

5.06.3.5 Reactions of Acetylation 153

5.06.3.6 Conjugations with Coenzyme A and Subsequent Reactions 155

5.06.3.6.1 Xenobiotic acyl-CoA conjugates as metabolic crossroads 155

5.06.3.6.2 Amino acid conjugation 155

5.06.3.6.3 Formation of hybrid triacylglycerides and cholesteryl esters 157

5.06.3.6.4 Chiral inversion and b-oxidation 157

5.06.3.7 Conjugations with Glutathione 158

5.06.3.7.1 Glutathione and glutathione transferases 158

5.06.3.7.2 Substrates of glutathione transferases 160

5.06.4 Conclusion 162 References 163

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