Phase II Conjugation Enzymes

Phase II conjugation enzymes attach an endogenous chemical group - such as glucuronic acid, sulfate, glutathione, or an acetyl group - to a drug or its phase I metabolite, making it more water-soluble and easier to excrete. These transferase enzymes, including the UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, N-acetyltransferases, and thiopurine S-methyltransferase, are an important and genetically variable arm of drug metabolism.

Definition

Phase II conjugation enzymes are transferase enzymes that covalently attach an endogenous moiety (such as glucuronic acid, sulfate, glutathione, an acetyl group, or a methyl group) to a drug or its metabolite, generally increasing water solubility and promoting elimination.

Scope

This topic covers the major phase II (conjugation) enzyme families, the conjugation reactions they catalyse, and the pharmacogenomic consequences of their genetic variation. It is a reference description of mechanisms and does not give dosing or treatment instructions.

Core questions

• Which conjugation reactions and enzyme families make up phase II metabolism?
• How does genetic variation in conjugating enzymes affect drug elimination and toxicity?
• When does conjugation inactivate a drug versus alter its disposition in other ways?

Key concepts

• Glucuronidation (UDP-glucuronosyltransferases, UGTs)
• Sulfation (sulfotransferases, SULTs)
• Glutathione conjugation (glutathione S-transferases, GSTs)
• Acetylation (N-acetyltransferases, NAT1/NAT2)
• Methylation (e.g., thiopurine S-methyltransferase, TPMT)
• Cofactor-dependent transfer of an endogenous group
• Genetic polymorphism and enzyme deficiency

Mechanisms

Phase II enzymes catalyse the transfer of an endogenous group from a cofactor onto a functional group on the drug or its phase I metabolite. Glucuronidation, the most prominent route, is performed by the UDP-glucuronosyltransferases using UDP-glucuronic acid; other routes include sulfation, glutathione conjugation, acetylation, and methylation (Tukey & Strassburg, 2000). The added group usually increases water solubility and abolishes pharmacological activity, facilitating biliary or renal excretion (Wilkinson, 2005). Several of these enzymes are markedly polymorphic, so inherited deficiency or reduced activity can slow elimination and increase exposure - a classic pharmacogenomic example being reduced thiopurine S-methyltransferase activity affecting thiopurine handling (Evans & McLeod, 2003).

Clinical relevance

Variation in phase II conjugation explains part of the interindividual difference in drug exposure and, for some drugs, the risk of accumulation when a conjugating enzyme is deficient. This entry describes those mechanisms as reference material and is not a basis for individual dosing or treatment decisions.

Epidemiology

Genetic deficiencies in phase II enzymes vary in frequency across populations; for example, the proportions of slow and rapid acetylators (reflecting NAT2 variation) and of low-activity thiopurine S-methyltransferase carriers differ by ancestry, contributing to population differences in drug handling (Evans & McLeod, 2003).

History

Conjugation was recognised as the second of R. T. Williams's two phases of drug metabolism, and the individual transferase families were progressively cloned and characterised through the late twentieth century. Pharmacogenetic discoveries - notably acetylation polymorphism and thiopurine S-methyltransferase deficiency - established phase II enzymes as a source of clinically meaningful inherited variation, with the UDP-glucuronosyltransferases reviewed in detail by Tukey and Strassburg (2000).

Key figures

• Robert Tukey
• Christian Strassburg
• Grant Wilkinson
• William Evans
• Howard McLeod

Seminal works

• tukey-strassburg-2000
• evans-mcleod-2003

Frequently asked questions

What does conjugation do to a drug?

It attaches an endogenous chemical group to the drug or its metabolite, usually making the molecule more water-soluble and pharmacologically inactive so the body can excrete it more readily.

Why does a phase II enzyme deficiency matter?

If a conjugating enzyme has reduced or absent activity because of genetic variation, a drug that depends on that enzyme may be eliminated more slowly and accumulate, which can increase the risk of dose-related effects for the affected medicines.