A NAcetylation NAT2

Differences in this metabolism phenotype were first identified in the late 1940s when patients who converted to a positive tuberculin test were routinely treated with isoniazid. A high incidence of peripheral neuropathy was found among those taking isoniazid. By giving isoniazid and measuring plasma levels 6 hours later (Figure 4.1), individuals could be phenotyped as slow acetylators (r, clearing the drug slowly) or rapid acetylators (R, clearing the drug quickly). The slow phenotype is inherited as an autosomal recessive trait. The frequency of the r allele was found to be about 0.72 in the United States, meaning that about one in every two individuals (using the Hardy-Weinberg equation, q2 = 0.72 x 0.72 = 0.518) is homozygous for r/r and thus shows the slow acetylator trait.

Two human N-acetyltransferase functional genes (NAT1, NAT2) were discovered, and the NAT2 gene was found to be responsible for the rapid and slow acetylator phenotypes. It was (somewhat arbitrarily) decided to name the reference (wild-type) allele (NAT2*4) as the one encoding the rapid acetylator enzyme. Three major NAT2 slow acetylator variant alleles exist: NAT2*5B and NAT2*6A are common in Caucasians; NAT2*6A and NAT2*7A are common in Asians. There are now at least 24 other, relatively rare, NAT2 alleles that have been discovered.22 Large ethnic differences exist in the frequency of the rapid and slow acetylator alleles. For example, the slow acetylator homozygote frequency ranges worldwide from less than 10% in Japanese populations to more than 90% in Egyptians.8

Although the N-acetylation polymorphism represents predominantly one gene, i.e. NAT2, Figure 4.1 shows plasma concentrations ranging from 0.3 to 11.8 ^g per ml, in other words, about a 30-fold difference between the extreme individuals although the average rapid and slow acetylators showed about 1.0 and 5.0 ^g per ml, respectively. This gradient, as opposed to

Table 4.1 One Possible Classification of Human Ecogenetic Disorders

A. Less enzyme/defective protein

1. N-acetylation (NAT2, NAT1)

2. Glucose-6-phosphate dehydrogenase (G6PD)

3. P450 monooxygenases (oxidation deficiencies) debrisoquine (CYP2D6), S-mephenytoin (CYP2C19 & CYP2C9), nifedipine (CYP3A4), coumarin and nicotine (CYP2A6), theophylline (CYP1A2), acetaminophen (CYP2E1), CYP1A1, CYP2B6

4. Null mutants of glutathione transferase, mu class (GSTM1); theta class (GSTT1)

5. Sulfotransferases (SULT)

6. Thiopurine methyltransferase (TPMT)

7. Thiol methyltransferase (THMT)

8. Catechol O-methyltransferase (COMT)

9. Paraoxonase, sarinase deficiency (PON1)

10. UDP glucuronosyltransferases (Gilbert's disease, UGT1A1; [S]-oxazepam, UGT2B7)

11. NAD(P)H:quinone oxidoreductase (NQO1)

12. Microsomal, soluble epoxide hydrolases (EPHX1, EPHX2)

13. Aldehyde dehydrogenase (ALDH2)

B. Alteration in receptor, transporter or channel protein

1. Inability to taste phenylthiourea

2. Coumarin anticoagulant resistance (receptor-based?)

3. Long-QT syndrome (KVLQT1, HERG, KCBMB1, KCNMB2, SCN5A)

4. Malignant hyperthermia/general anesthesia (defect in Ca++-release channel ryanodine receptor) (RYR1)

5. Cyanocobalamine (vitamin B12 malabsorption), absence of intrinsic factor

6. b-Adrenergic receptors (ADRB1, ADRB2, ADRB3) and sensitivity to b-agonists in asthmatics

C. Change in response due to enzyme induction, overexpression

1. Porphyrias (esp. cutanea tarda)

2. Aryl hydrocarbon receptor (AHR) (CYP1A1, CYP1A2, CYP1B1 inducibility) cancer, immunosuppression, birth defects, chloracne, porphyria, (?)eye toxicity, (?)ovarian toxicity

D. Abnormal metal distribution

1. Iron (hereditary hemochromatosis, HFE)

2. Copper (Wilson disease, Menkes disease)

3. Cadmium toxicity (CDM)

4. Lead toxicity and 5-aminolevulinate dehydratase (ALAD)

E. Disorders of unknown etiology

1. Corticosteroid (eye drops)-induced glaucoma

2. Halothane-induced hepatitis

3. Chloramphenicol-induced aplastic anemia

4. Phenytoin-induced gingival overgrowth

5. Aminoglycoside antibiotic-induced deafness

6. Methotrexate-induced toxicity in juvenile rheumatoid arthritis

7. L-DOPA-induced dyskinesis in Parkinson disease

8. Glucosidation of amobarbital

9. Beryllium-induced lung disease

10. Bleomycin-induced pulmonary toxicity

11. Myocardial toxicity by anthracyclines (adriamycin, doxorubicin)

Figure 4.1 Plasma isonazid concentrations 6 hours after the drug was given. Results were obtained in 267 members of 53 complete family units. All subjects received approximately 9.8 mg isoniazid per kg body weight. (Modified from Price-Evans, D.A., Manley, K., and McKusick, V.A., Brit. Med. J., 2, 485-498, 1960.)

extremely highly defined peaks and valleys, would suggest that modifier genes encoding enzymes or other proteins (or environmental factors including other drugs given to these patients) might influence plasma isoniazid concentrations.

The association of acetylation phenotypes with toxicity or cancer has received considerable attention. The slow acetylator phenotype shows a threefold lower incidence of colorectal carcinoma but a higher incidence (odds ratio = at least 16) of bladder cancer.12 Occupational exposure to arylamines and cigarette smoking are required, however, in conjunction with the slow acetylator phenotype for bladder cancer to occur. No relationship is found between acetylator phenotype and smoking-related bladder cancer in the absence of exposure to arylamines or cigarette smoking.

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