Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary diseases
Pharmacogenetic enzymopathies

Pharmacogenetics is the branch of science that investigates the GENETIC BASIS OF drug response. If a medicinal product causes adverse effects such as enzymatic idiosyncrasies regardless of the dose, this is a consequence of latent pharmacogenetic enzymopathy. Drug-metabolizing Enzymes in the body undergo two stages: prenatal development and postnatal maturation. Due to the immaturity of the protein-synthesizing apparatus of hepatocytes in the first months after birth, every genetically healthy child should be considered an Organism suffering from temporary pharmacogenetic enzymopathy. This must be taken into account when prescribing drug therapy to children under 3–6 months of age, especially during the neonatal period and even more so in premature infants.

Pharmacogenetic enzymopathy may manifest as unusual adverse effects, symptoms of poisoning, or varying degrees of drug resistance. Such phenomena result from a mutation in the Gene encoding enzymes or modifying its action, or from other disruptions in regulatory Regions of the genome. There are receptor-dependent forms of altered, genetically determined responses to medications. This pathology is usually detected accidentally upon the prescription of a specific drug therapy. Once a proband's susceptibility to dose-independent adverse reactions to a particular drug is identified, all their relatives should be purposefully examined to detect hidden pharmacogenetic enzymopathy.

Among pharmacogenetic enzymopathies, the following are particularly noteworthy.

N-acetyltransferase deficiency, which is responsible for the Acetylation of medicinal products. This causes hypersensitivity to isoniazid (isonicotinic acid hydrazide, INAH) and its slow inactivation. INAH enzymopathy leads to polyneuritis and epileptic seizures. Under these pathological conditions, Apressin can cause a severe condition resembling systemic lupus erythematosus. The donor of N-acetyltransferase is pantothenic acid, which is scarce in the diet of newborns.

It is precisely this circumstance and enzyme immaturity that cause a temporary (up to 5 months) pharmacogenetic deficiency in the child regarding this enzyme. Currently, The Role of N-acetyltransferase deficiency in the Pathogenesis of Diabetes Mellitus and gastric ulcers is a subject of scientific debate. It exhibits an AR inheritance pattern.

Acatalasemia is the first pharmacogenetic enzymopathy described in the literature, characterized by hypersensitivity to ethanol and resistance to methanol. In the absence of catalase, peroxide Hydrolysis does not occur, the mechanism preventing methemoglobin formation fails to function, hemolysis occurs under the action of oxidizing agents, and sensitivity to gamma rays increases. In Japanese and Korean families, acatalasemia is associated with Takahara's disease, which manifests as oral tissue gangrene and Sepsis. In Germany, a case of periodontitis in a 4-year-old child caused by acatalasemia has been described. Capsules containing plant-derived catalase are used as replacement therapy for this pathology. It exhibits an AR inheritance pattern.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency manifests as hemolytic crises in response to the administration of primaquine, sulfanilamide, phenacetin, phenylhydrazine, etc. Worldwide, about 200 million people suffer from this pathology, predominantly males. The gene is recessive and located on the X chromosome, so the pathology is inherited in an XR pattern. However, the gene product is part of The erythrocyte membrane, which has a clonal origin (from a single Cell). In females, random hyper-spiraling of one of the X Chromosomes occurs, leading to hemizygosity for one of the G6PD alleles in different Cells of heterozygous females. If the majority of erythrocytes originate from a stem cell with an active X chromosome carrying the mutant G6PD allele, the woman is sensitive to the aforementioned drugs. She experiences hemolysis, headaches, and Skin yellowishness. After discontinuing the medications, the patient recovers.

Individuals with G6PD deficiency are sensitive to certain foods and non-medicinal substances: fava beans (favism), red currants, gooseberries, and naphthalene. Neonatal Hyperbilirubinemia is largely caused by a temporary deficiency of this enzyme.

Glutathione reductase deficiency manifests in cases of Mushroom poisoning and after Gallbladder removal. This enzyme is part of the erythrocyte membrane and is involved in the METABOLISM of certain heavy metals, such as thallium. Such a disorder can cause hypersensitivity to thallium (nasopharyngitis, Nervous system damage, hallucinations, alopecia). An AD inheritance pattern is characteristic. Enzyme efficiency increases in Gout, diabetes mellitus, and in newborns.

Methemoglobin reductase deficiency is accompanied by cyanosis, persistence of HbF, and hypersensitivity to nitrates and nitrites. Temporary latent enzymopathy of this type most commonly manifests in children under 3 months of age.

When mutant alleles of the cholinesterase gene are present, individuals (predominantly Eskimos) are sensitive to the Muscle relaxant suxamethonium (dithylin), the administration of which leads to respiratory arrest and death. Resistance to this drug is observed in Schizophrenia.

The elimination of certain drugs from the body involves their mandatory conversion into Water-soluble mono- and diglucuronide forms. This is carried out with the help of uridine diphosphate glucuronosyltransferase, which is synthesized in The Liver and Functions in the liver, Kidneys, Brain, and intestinal mucosa. Antibiotics (novobiocin, biomycin, levomycetin), sulfonamides, barbiturates, opiates, phenacetin, pyramidon, menthol, camphor, phenolphthalein, bilirubin, Vitamins (nicotinic acid), Hormones (estrogens, androgens, corticosteroids, triiodothyronine, adrenaline), serotonin, Cholesterol, and Certain Amino Acids are eliminated from the body according to this scheme. The enzyme inhibitor pregnanediol worsens the temporary neonatal enzymopathy related to uridine diphosphate glucuronosyltransferase. Consequently, levomycetin causes Gray syndrome in newborns: severe poisoning on the 3rd to 9th day after antibiotic administration, accompanied by vomiting, abdominal tension, diarrhea, cyanosis, shortness of breath, and lowered Blood pressure. In some cases, death occurs. Therefore, levomycetin can be prescribed to newborns only for vital indications at a daily dose of no more than 25 mg per 1 kg of body weight. Stimulators of glucuronide conjugation include vitamin B₁₂, cordiamine, and phenobarbital. It exhibits an AR inheritance pattern.

Drug intolerance may also be associated with a genetic defect in Blood Plasma Proteins (primarily albumin), which transport drugs to Organs in a bound state. Only free medicinal products exert a therapeutic effect. Binding to albumin serves as a form of storage, during which drugs (sulfonamides, salicylic acid, synthetic vitamin K) compete with bilirubin. The binding capacity of plasma proteins depends on age, which must be considered in the perinatal period and when treating elderly patients.

Genetically determined drug resistance can be enzymatic (as discussed above) or receptor-mediated. The latter results from Mutations in genes encoding specific cellular receptors or regulating the expression of these genes (in cases of resistance to atropine, morphine, coumarin anticoagulants, and calciferol). Hereditary predisposition should be distinguished from tachyphylaxis (tolerance), in which the induction of drug-metabolizing enzymes occurs.

Due to the temporary pharmacogenetic enzymopathy of the newborn, as well as the frequency and severity of pathological reactions to drug therapy, all medicinal products are divided into 3 groups: 1) those indicated for use in the neonatal period (benzylpenicillin, methicillin sodium, oxacillin sodium, ampicillin, erythromycin, oleandomycin phosphate, cephaloridine, cephalexin, claforan, nystatin, caffeine, cerucal, phenobarbital, vicasol, seduxen, sodium oxybutyrate, piracetam); 2) those requiring caution in use (atropine sulfate, aminazine, analgin, digoxin, strophanthin, D-penicillamine, theophylline, euphyllin, gentamicin, amikacin, lincomycin hydrochloride); 3) agents contraindicated in the neonatal period (boric acid, levomycetin, Tetracyclines, kanamycin, monomycin, nalidixic acid, sulfonamides, narcotic analgesics — the morphine group).

The science of pharmacogenetics emerged in the 1960s after a portion (about 20%) of pregnant women in Europe who took the drug thalidomide (also known as softenon) gave birth to children with congenital limb defects (phocomelia). This observation taught science two lessons: the consequences can only be realized several years after the Introduction of a new drug into mass medical practice; testing pharmacological agents in model systems (even in mammals) may not always be adequate because humans differ in genotype from animals. Thalidomide did not cause teratogenesis in animal experiments.

Amidst market oversaturation with new medicinal products, it is necessary to monitor their potential negative pharmacogenetic impact, which may vary in frequency from population to population due to their differing gene pools. Particular caution should be exercised when using complex regimens of new drugs during the therapy of newborns and the elderly.

Nowadays, some of the main problems of pharmacogenetics include determining the role of pharmacogenetic factors in the onset of amidopyrine-induced agranulocytosis, clarifying the relationship between pharmacogenetic defects and allergies, and investigating The Influence of genotype on The Development of alcoholism, nicotine dependence, and drug addiction.