Genetics · MU Sofia

58. Pharmacogenetics and pharmacogenomics. Polymorphic monogenic pharmacogenetic defects. G6PD-deficiency; deficiency of: TPMT, DPYD, NAT1, and NAT2; alcohol dehydrogenase and aldehyde dehydrogenase deficiency.

Covers polymorphic monogenic pharmacogenetic defects and then works through G6PD, TPMT, DPYD, NAT1/NAT2 and ADH/ALDH deficiencies in turn, giving for each the inheritance or genetic background, the mechanism leading to toxicity, the drugs affected and the clinical features. Includes a short table on slow and fast acetylator phenotypes and step-by-step pathophysiology lists for each defect.

Inside: 7 sections · 12 labelled pictures · 1 table · 14 flashcards · 4 min

Topic 58 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 7 sections, about 564 words (4 min of reading), with 14 flashcards.

In this note

  1. Pharmacogenetics and pharmacogenomics. Polymorphic monogenic pharmacogenetic defects. G6PD-deficiency; deficiency of: TPMT, DPYD, NAT1, and NAT2; alcohol dehydrogenase and aldehyde dehydrogenase deficiency.
  2. I. GENERAL CONCEPT
  3. II. G6PD DEFICIENCY
  4. III. TPMT DEFICIENCY (THIOPURINE METHYLTRANSFERASE)
  5. IV. DPYD DEFICIENCY (DIHYDROPYRIMIDINE DEHYDROGENASE)
  6. V. NAT1 AND NAT2 DEFICIENCY (N-ACETYLTRANSFERASES)
  7. VI. ALCOHOL DEHYDROGENASE (ADH) AND ALDEHYDE DEHYDROGENASE (ALDH) DEFICIENCY

I. GENERAL CONCEPT

What is meant by polymorphic pharmacogenetic defects?

Polymorphic monogenic pharmacogenetic defects are caused by common genetic variants (polymorphisms) in single genes that influence:

  • drug metabolism,
  • drug efficacy,
  • risk of adverse drug reactions.

Unlike rare pharmacogenetic disorders, these variants are frequent in the general population and explain inter-individual differences in drug response.

Pharmacogenetic Mechanisms

  1. 1. Altered enzyme activity (reduced, absent, or increased).
  2. 2. Changes in drug clearance.
  3. 3. Accumulation of toxic metabolites.
  4. 4. Increased sensitivity or resistance to drugs.

II. G6PD DEFICIENCY

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a pharmacogenetic disorder characterized by increased susceptibility to oxidative stress, leading to hemolytic anemia after exposure to certain drugs or substances.

Inheritance

  • X-linked recessive
  • Males more severely affected
  • Females may be carriers or variably affected due to lyonization

Normal Function of G6PD

G6PD is a key enzyme of the pentose phosphate pathway, producing NADPH, which:

  • maintains glutathione in reduced form,
  • protects red blood cells from oxidative damage.

RBCs are especially vulnerable because they lack mitochondria.

Pathophysiology

  1. 1. G6PD activity is reduced.
  2. 2. NADPH production decreases.
  3. 3. Reduced glutathione cannot neutralize oxidative stress.
  4. 4. Oxidative damage to hemoglobin and RBC membrane occurs.
  5. 5. Hemolysis is triggered after exposure to oxidant drugs or infections.

Triggering Agents

  • Antimalarials (e.g., primaquine)
  • Sulfonamides
  • Nitrofurantoin
  • Certain antibiotics
  • Fava beans
  • Infections

Clinical Features

  • Acute hemolytic anemia
  • Jaundice
  • Dark urine
  • Fatigue
  • Neonatal jaundice (severe cases)

Clinical Importance

G6PD deficiency is one of the most important pharmacogenetic conditions worldwide and a classic example of drug-induced hemolysis.

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