Genetic Variability In Drug Metabolizing Enzymes

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Polymorphisms have now been identified in more than 20 human drug metabolizing enzymes, often with diverse frequencies in various ethnic groups (33). These include both the Phase I (which are largely P450 enzymes) and Phase II (including glucuronyl transferases, N-acetyltransferases, sulfotransferases, and glutathione transferases) enzymes. Polymorphisms in the genes encoding these enzymes usually lead to a loss of

Figure 1 The interplay between genetic and environmental factors in the predisposition to adverse drug reactions.

Table 1 Examples of Adverse Drug Reactions Associated with Genetically Determined Variation in Drug Pharmacokineticsa

Gene symbol

Title

Drug

Adverse reaction

BCHE, CHE1

Butyrylcholinesterase

Succinylcholine

Prolonged apnea after

anesthesia

Butyrylcholinesterase

Cocaine

Increased toxicity

CYP2C9

Cytochrome P450 2C9

Warfarin

Bleeding

CYP1A2

Cytochrome P450 1A2

Phenacetin

Hypersensitivity

CYP2D6

Cytochrome P450 2D6

Codeine

Increased respiratory,

psychomotor, and

pupillary effects

GSTM1 and

Glutathione-S-transferase

Tacrine

Transaminitis

GSTT1

GSTM1

Glutathione-S-transferase

Cisplatin

Ototoxicity

GSTM1 and

Glutathione-S-transferase

Troglitazone

Hepatotoxicity

GSTT1

NAT-2

N-acetyltransferase

Sulfasalazine

Vomiting

N-acetyltransferase

Isoniazid

Peripheral neuropathy

N-acetyltransferase

Procainamide

SLE

UGT1A

Glucuronyltransferase

Tolcapone

Hepatotoxicity

Glucuronyltransferase

Irinotecan

Neutropenia

Glucuronyltransferase

Tranilast

Hyperbilirubinaemia

DIA1

Methemoglobin reductase

Nitrites, dapsone

Methaemoglobinemia,

hemolysis

PBGD

Porphobilinogen

Barbiturates,

Acute porphyric crises

deaminase

anticonvulsants,

sulfonamides

ACHE

Acetylcholinesterase

Pyridostigmine

Neurotoxicity

aMany of these associations have only been shown in single studies and/or may not have been replicated. Abbreviation: SLE, systemic lupus erythematosus.

aMany of these associations have only been shown in single studies and/or may not have been replicated. Abbreviation: SLE, systemic lupus erythematosus.

Table 2 Examples of Adverse Drug Reactions Associated with Genetically Determined Variation in the Pharmacodynamic Effects of Drugsa

Gene symbol Name

HERG (KCNH2), KvLQTl (KCNQl), Mink (KCNEl), MiRPl (KCNE2) RYR1

OPRMl G6PD

DRD3, HTR2A

HTR2C

BKR2 F2 and F5

Drug

Erythromycin, terfenadine, cisapride clarithromycin, quinidine, sulfamethoxazole

General anesthetics (halothane plus succinylcholine) Morphine Primaquine, sulfonamides, dapsone Clozapine

Oral contraceptives Warfarin

Adverse reaction

Increased risk of torsade de pointes, drug-induced long QT syndrome

Malignant hyperthermia

Addiction Hemolytic anemia

Tardive dyskinesia

Increased risk of deep vein and cerebral vein thrombosis Sensitivity, bleeding

Potassium voltage-gated channels

Ryanodine receptor

Mu-opioid receptor Glucose-6-phosphate dehydrogenase Dopamine D3

receptor, Serotonin 5-HT-2A Serotonin 5-HT-2C

receptor Angiotensin I-converting enzyme Bradykinin receptor B2

Prothrombin and Factor V

Clozapine

ACE inhibitors

ACE inhibitors

Weight gain Cough

Cough

Factor IX

aMany of these associations have only been shown in single studies and/or may not have been replicated. Abbreviation: ACE, angiotensin-converting enzyme.

function, although occasionally, gain of function may occur. Alternatively, a polymorphism may lead to alteration in substrate specificity—this has been described for the P450 enzymes CYP2D6 and CYP2C9 (34-36). In general, variability in drug metabolism may lead to an ADR through one or more of the following mechanisms (25) (which are not mutually exclusive):

1. Increased concentration of the drug as a result of deficient metabolism leading to a dose-dependent ADR;

2. Deficient enzyme activity results in rerouting of metabolism leading to an ADR;

3. Exaggerated drug response as a result of increased metabolism when the drug effect is dependent on the active metabolite rather than the parent drug;

4. Variability in the formation of the reactive metabolite leading to idiosyncratic drug toxicity; and

5. Decreased bioinactivation of the reactive metabolite as a result of a deficiency in detoxication.

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