Genetic Polymorphism and Drug Metabolism

Genetic polymorphism in drug-metabolizing enzymes is one of the best-characterized sources of variability in how the body processes medicines. Common inherited variants in genes such as the cytochrome P450 family, thiopurine S-methyltransferase, and UDP-glucuronosyltransferases can speed up, slow down, or abolish the metabolism of their substrate drugs, changing the amount of active compound that circulates. This topic addresses how such polymorphisms arise and how they translate into pharmacokinetic differences.

Definition

Genetic polymorphism in drug metabolism is the occurrence of two or more inherited variant forms of a drug-metabolizing-enzyme gene at appreciable frequency in a population, where the variants alter enzyme quantity or function and thereby change the rate at which substrate drugs are biotransformed.

Scope

The topic covers the nature of genetic polymorphism in genes governing drug metabolism, the distinction between phase I (oxidative) and phase II (conjugative) enzymes, the functional consequences of common variants, and the principle that the same gene can carry many variant alleles with differing activity. It is framed as a reference concept and excludes drug-specific dosing instructions.

Core questions

• Which inherited variants in drug-metabolizing-enzyme genes alter enzyme activity, and how?
• How do phase I and phase II metabolic polymorphisms differ in their effect on drug handling?
• How does a change in metabolizing-enzyme activity translate into altered drug exposure?
• Why does the same enzyme gene carry so many functionally distinct alleles?

Key concepts

• Phase I (oxidative) and phase II (conjugative) metabolism
• Cytochrome P450 enzyme family (e.g., CYP2D6, CYP2C19, CYP2C9)
• Loss-of-function and gain-of-function alleles
• Gene duplication and copy-number variation
• Substrate, prodrug, and active-metabolite relationships
• Enzyme activity gradient from absent to increased
• Multiple variant alleles within a single gene

Mechanisms

Polymorphisms in metabolizing-enzyme genes act through several routes: missense variants can change enzyme structure and catalytic efficiency; splice-site, frameshift, or nonsense variants can produce non-functional protein; regulatory or copy-number variants (including whole-gene duplication or deletion) can raise or lower the amount of enzyme made. Because many drugs are activated or inactivated by these enzymes, reduced activity can let parent drug accumulate or prevent a prodrug from being converted to its active form, while increased activity can clear a drug too quickly to be effective. The net pharmacokinetic effect depends on whether the drug itself or a downstream metabolite is the active species.

Clinical relevance

Polymorphic drug metabolism underlies many observed differences in drug exposure and is a principal reason that genotype-based prediction of metabolic capacity is studied in pharmacogenomics. As reference material this topic explains why metabolism varies between individuals; it is not a source of dosing guidance, which must come from validated clinical guidelines applied by qualified clinicians using a patient's full clinical picture.

Epidemiology

Functionally important metabolizing-enzyme variants are common, and their frequencies differ substantially across ancestral populations, so the proportion of poor, normal, or rapid metabolizers for a given enzyme varies by population. This variation contributes to population differences in drug exposure and in the risk of dose-related effects.

History

The recognition that drug metabolism is heritable grew from family studies of slow isoniazid acetylation and of inherited thiopurine methyltransferase deficiency in the mid-twentieth century. The subsequent molecular characterization of the cytochrome P450 genes and their variant alleles turned these clinical observations into a defined genetic framework, which Evans and Relling and later reviews placed at the centre of pharmacogenomics.

Key figures

• Richard Weinshilboum
• William Evans
• Howard McLeod
• Werner Kalow

Seminal works

• weinshilboum-2003
• evans-1999
• mcleod-2001

Frequently asked questions

What is the difference between a polymorphism and a mutation in drug-metabolism genes?

Both are DNA sequence variants; the term polymorphism conventionally describes a variant common in the population (often above about 1 percent), whereas mutation is often used for rarer or disease-causing changes, though the underlying molecular event can be the same.

Why can a single drug be affected by more than one metabolic polymorphism?

Many drugs are processed by several enzymes in sequence or in parallel, so variants in more than one metabolizing gene, plus transporter variants, can each contribute to how much active drug a person is exposed to.