Which enzyme's activity includes normal, poor, and ultra-rapid metabolizer phenotypes?

Which enzyme's activity includes normal, poor, and ultra-rapid metabolizer phenotypes?

• A. CYP2D6
• B. CYP3A4
• C. CYP1A2
• D. CYP2C9

Answer: (A)

Genetic variability in drug-metabolizing enzymes can create a range of metabolic phenotypes from poor to ultra-rapid. The enzyme that best exemplifies all four phenotypes—poor, intermediate, normal, and ultra-rapid metabolizers—is CYP2D6. This is because its gene has many different alleles, including loss-of-function variants and gene duplications, leading to very low, reduced, normal, or highly increased enzyme activity across individuals. This wide variation matters clinically because drugs metabolized by CYP2D6 can behave very differently depending on a person’s metabolizer status. For example, codeine needs CYP2D6 to be converted into its active form, morphine. Ultra-rapid metabolizers can rapidly convert more codeine to morphine, risking toxicity, while poor metabolizers may not achieve adequate analgesia due to insufficient activation. Other enzymes like CYP3A4, CYP1A2, or CYP2C9 have polymorphisms too, but they don’t demonstrate the same clear spectrum of ultra-rapid metabolism to the same extent as CYP2D6.

Genetic variability in drug-metabolizing enzymes can create a range of metabolic phenotypes from poor to ultra-rapid. The enzyme that best exemplifies all four phenotypes—poor, intermediate, normal, and ultra-rapid metabolizers—is CYP2D6. This is because its gene has many different alleles, including loss-of-function variants and gene duplications, leading to very low, reduced, normal, or highly increased enzyme activity across individuals.

This wide variation matters clinically because drugs metabolized by CYP2D6 can behave very differently depending on a person’s metabolizer status. For example, codeine needs CYP2D6 to be converted into its active form, morphine. Ultra-rapid metabolizers can rapidly convert more codeine to morphine, risking toxicity, while poor metabolizers may not achieve adequate analgesia due to insufficient activation.

Other enzymes like CYP3A4, CYP1A2, or CYP2C9 have polymorphisms too, but they don’t demonstrate the same clear spectrum of ultra-rapid metabolism to the same extent as CYP2D6.