Yusuf, Wan Nazirah Wan
(2006)
An Investigation Of The
Genetic Polymorphisms Of
N-Acetyltransferase 2 In Healthy
Malays, Chinese And Indians In Malaysia
And In Tuberculosis Patients On
Isoniazid.
Masters thesis, Perpustakaan Hamzah Sendut.
Abstract
N-acetyltransferases are enzymes found in the liver, the small intestines,
urinary bladder, lungs and skin. They mediate Phase II metabolism of
xenobiotics containing an aromatic amine or a hydrazine group. They are
genetically polymorphic with several important SNP's. Their substrates include
INH, pro-carcinogens and carcinogens. They therefore have importance in the
pathogenesis of some cancers and in the pharmacotherapy of some diseases,
notably tuberculosis.
The objective of our study is to investigate the types and frequencies of
NAT2 polymorphisms in the three major ethnic groups in Malaysia and among
TB patients to forecast their influence on the rate of metabolism of INH.
Malay, Chinese and Indian healthy volunteers were recruited from blood
donation drives and their blood was taken for NAT2 genotyping. Newly
diagnosed TB patients were also recruited. Blood for genotyping and
phenotyping were collected at 4 hours after INH ingestion in patients who were
treated with INH. Genotyping was done using nested allele specific multiplex
peR methods and phenotyping by measuring plasma INH and Act-INH on the
HPLC.
Among healthy volunteers, the frequencies for NAT2*4, NAT2*5, NAT2*6,
NAT2*7 and NAT2*12 in the 212 Malays, 172 Chinese and 175 Indians were 43.4%, 10.6%,25.5%,16.3% and 4.3% respectively among Malays; 64.0%,
3.2%,16.3%,12.2% and 0.3% among Chinese; and 22.6%,30.6%,30.9%,
6.9% and 3.4% among Indians. The types and frequencies for NAT2 alleles in
TB patients were NAT2*4, NAT2*5, NAT2*6, NAT2*7 and NAT2*12 at 47.4%,
14.0%,21.2%, 12.9% and 2.3% respectively. The most common genotypes
were NAT2*4/*4, NAT2*41*7, NAT2*4/*5 and NAT2*6/*6 with the frequencies of
25%, 18.9%, 15.2% and 15.2% respectively. There was no significant difference
in allele frequencies of TB patients and healthy volunteers. For the 62 patients
phenotyped, INH concentrations ranged from 0.31 to 4.17 j.Jg/ml and for Act-INH
concentration from 0.01 to 2.48 j.Jg/ml. There was a trend for the metabolic
ratios to increase with genotypes that predicted poorer activity. Correlation of
genotype to MR was however imperfect.
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