The arylamine N-acetyltransferase (NAT2) polymorphism and the risk of adverse reactions to co-trimoxazole in children.

摘要

OBJECTIVE: The evaluation of the importance of the genetically determined acetylation defect for the development of adverse reactions to co-trimoxazole in children. METHODS: The study comprised 48 children aged 3 months to 3 years, who were being treated for interstitial pneumonia with co-trimoxazole. During the treatment, daily clinical examinations and biochemical tests to monitor the functions in various organs enabled us to detect adverse reactions to the drug. The therapy was continued or discontinued according to the results of these examinations. In all children we identified the genotype coding for N-acetyltransferase (NAT2). For this purpose, DNA was isolated from peripheral blood. Polymerase chain reaction (PCR) was then carried out, followed by restriction mapping with the KpnI, Ddel, TaqI, and BamHI endonucleases in order to identify the four mutations at the NAT2 gene locus: 481C-->T; 803A-->G; 590G-->A and 857G-->A, respectively. RESULTS: In 29 children (60%) various adverse effects occurred and in 19 children (40%) no adverse reactions to treatment occurred. We found statistically significant differences in the occurrence of the identified wt alleles, and alleles with 590A and 857A mutations between the two groups of children studied. In the group with adverse effects, 87% of children had genotype coding for slow acetylation and only 13% had genotypes containing the wt allele. In the group without adverse effects the results were reversed: 89% had genotypes with the wt allele, and only 2 children (10%) were found to have the homozygotic mutation (slow acetylation). CONCLUSION: The results show that the occurrence of adverse effects from co-trimoxazole is closely connected with the genotype coding for slow acetylation.