«Slow acetylator» phenotype (N-acetyltransferase deficiency)
One of the most prominent examples of genetic polymorphism is the variability in the function of hepatic N-acetyltransferase. This enzyme is responsible for the metabolism of drug substances via acetylation reactions.
In clinical practice, a significant group of patients is identified who exhibit a congenital deficiency of this enzyme. Such individuals are commonly referred to as «slow acetylators». The main pharmacological problem of this phenomenon is that reduced enzyme activity leads to a critical delay in the elimination of drugs from the body. As a consequence, a therapeutic dose can become toxic, resulting in a sharp increase in the incidence of undesirable adverse effects.
The main triggering agents metabolized via this pathway include:
- The antituberculosis drug isoniazid (Isoniazidum);
- The antiarrhythmic drug procainamide (Procainamidum);
- Various sulfonamides.
Epidemiologically, the «slow acetylator» status is extremely characteristic of the Caucasian race, encompassing up to half (50%) of the entire population in this group.
Hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency
Another critically important enzyme outside the cytochrome P-450 system is glucose-6-phosphate dehydrogenase, localized in erythrocytes. In the genetic deficiency of this enzyme, the administration of certain drugs triggers a specific pathogenetic cascade.
The basis of pathogenesis is the formation of toxic quinone, which directly affects red blood cells. This leads to massive destruction (hemolysis) of erythrocytes and the rapid development of the clinical picture of severe hemolytic anemia.
The following medicinal substances can provoke this life-threatening process:
- Antimalarial alkaloids: quinine (Chininum) and quinidine;
- Sulfonamide drugs (Sulfanilamidea);
- The antibiotic chloramphenicol (Chloramphenicolum).
This genetic anomaly has a pronounced geographical association. Deficiency is most commonly found in residents of tropical and subtropical regions of the globe, where the number of mutation carriers reaches 100 million people.
Prolonged apnea: plasma pseudocholinesterase deficiency
The third important example of polymorphism is associated with the function of plasma pseudocholinesterase. This enzyme plays a key role in the inactivation of depolarizing neuromuscular blockers, in particular — suxamethonium (Suxamethonium).
In patients with normal pseudocholinesterase activity, the period of muscle relaxation (neuromuscular blockade) after administration of suxamethonium is only 5–7 minutes. However, in individuals with a genetic deficiency of this enzyme, the clinical manifestation consists of a dangerous prolongation of muscle relaxation, which can last from 6 to 8 hours. During this period, the patient experiences persistent apnea (cessation of breathing), requiring prolonged mechanical ventilation.
From an epidemiological standpoint, plasma pseudocholinesterase deficiency is extremely rare among Caucasians (about 0.04% of the population), but is significantly more frequently detected in specific ethnic groups, for example, among Eskimos (up to 1%).
Briefly: answers to topical questions
Which enzymes outside the cytochrome P-450 system have clinically significant genetic polymorphism?
The following enzymes outside the cytochrome P-450 system have clinically significant genetic polymorphism:
- N-acetyltransferase — a liver enzyme whose deficiency leads to the «slow acetylator» phenotype.
- Glucose-6-phosphate dehydrogenase — an erythrocyte enzyme whose deficiency causes hemolytic anemia.
- Pseudocholinesterase — a plasma enzyme whose deficiency prolongs muscle relaxation.
- Dihydropyrimidine dehydrogenase — an enzyme associated with pyrimidine analogue toxicity.
- Uridine diphosphate glucuronosyltransferase 1A1 — an enzyme whose polymorphism is associated with irinotecan toxicity.
Which drugs are metabolized by hepatic N-acetyltransferase?
The following drugs are metabolized by hepatic N-acetyltransferase:
- Isoniazid (Isoniazidum).
- Sulfonamides.
- Procainamide (Procainamidum).
What specific adverse effects develop in «slow acetylators» when taking isoniazid?
When taking isoniazid, «slow acetylators» develop specific neurotoxic adverse effects associated with vitamin B6 deficiency.
- Peripheral neuropathy — neuritis arising due to the suppression of pyridoxal phosphate synthesis.
- Toxic effect on the brain — manifesting as memory loss, psychoses, and seizures.
The risk of these effects is due to the slowed elimination of the drug, a 4-to-6-fold increase in its plasma concentration, and the accumulation of the substance in the body.
Which medicinal substances cause erythrocyte hemolysis in glucose-6-phosphate dehydrogenase deficiency?
Erythrocyte hemolysis in glucose-6-phosphate dehydrogenase deficiency is caused by:
- Quinine (Chininum) and quinidine.
- Sulfonamides (Sulfanilamidea).
- Chloramphenicol (Chloramphenicolum).
- Primaquine.
- Paracetamol.
What is the biochemical mechanism of erythrocyte destruction in glucose-6-phosphate dehydrogenase deficiency?
The biochemical mechanism of erythrocyte destruction is due to the impairment of the pentose phosphate pathway and a decrease in NADPH production. Due to the lack of NADPH, glutathione reductase function is impaired, leading to a deficiency of reduced glutathione. As a result, reactive oxygen species oxidize the SH groups of hemoglobin. This causes the formation of disulfide bonds and hemoglobin aggregation with the formation of Heinz bodies. These inclusions damage the erythrocyte membrane, ultimately leading to its destruction and the development of hemolytic anemia.
To memorize the drugs causing hemolysis in G6PD deficiency, use the mnemonic: Quinine, Quinidine, Sulfonamides, Chloramphenicol.
Class and exam questions
What are the risks for a patient with the "slow acetylator" status?
In such patients, the elimination of drugs (isoniazid, procainamide) is slowed down, leading to their accumulation in the body and a sharp increase in the risk of adverse effects.
Why does prolonged apnea occur after the administration of suxamethonium?
The cause is a congenital deficiency of plasma pseudocholinesterase. Due to the lack of the enzyme, muscle relaxation is prolonged from the normal 5–7 minutes to 6–8 hours.
In which regions is glucose-6-phosphate dehydrogenase deficiency most prevalent?
This pathology is most frequently found in residents of tropical and subtropical regions, encompassing up to 100 million people worldwide.
What else to study on this topic
- Mechanisms of acetylation reactions in the liver
- Pathogenesis of quinone formation in erythrocytes
- Pharmacodynamics of depolarizing neuromuscular blockers
- Ethnic characteristics of drug metabolism
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