Para-phenylenediamine and allergic sensitization: risk modification by N-acetyltransferase 1 and 2 genotypes

Background Para-phenylenediamine (PPD) is a common contact sensitizer causing allergic contact dermatitis, a major skin problem. As PPD may need activation to become immunogenic, the balance between activation and/or detoxification processes may influence an individual's susceptibility. PPD is acetylated and the metabolites do not activate dendritic-like cells and T cells of PPD-sensitized individuals. Objectives To investigate whether PPD can be acetylated in vitro by the two N-acetyltransferases 1 (NAT1) and 2 (NAT2). Based on the assumption that N-acetylation by NAT1 or NAT2 is a detoxification reaction with respect to sensitization, we examined whether NAT1 and NAT2 genotypes are different between PPD-sensitized individuals and matched controls. Methods Genotyping for NAT1 and NAT2 polymorphisms was performed in 147 PPD-sensitized individuals and 200 age- and gender-matched controls. Results Both PPD and monoacetyl-PPD were N-acetylated in vitro by recombinant human NAT1 and to a lesser extent by NAT2. Genotyping for NAT1*3, NAT1*4, NAT1*10, NAT1*11 and NAT1*14 showed that genotypes containing the rapid acetylator NAT1*10 allele were under-represented in PPD-sensitized cases (adjusted odds ratio 0.72, 95% confidence interval 0.45-1.16). For NAT2, NAT2*4, NAT2*5AB, NAT2*5C, NAT2*6A and NAT2*7B alleles were genotyped. Individuals homozygous for the rapid acetylator allele NAT2*4 were under-represented in cases compared with controls (4.3% vs. 9.4%), but this trend was not significant. Conclusions With respect to data indicating that NAT1 but not NAT2 is present in human skin, we conclude that NAT1 genotypes containing the rapid acetylator NAT1*10 allele are potentially associated with reduced susceptibility to PPD sensitization.