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Urinary acetylated metabolites and N-acetyltransferase-2 genotype in human subjects treated with a para-phenylenediamine-containing oxidative hair dye

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Author: Nohynek, G.J. · Skare, J.A. · Meuling, W.J.A. · Hein, D.W. · Bie, A.T.H.J. de · Toutain, H.
Institution: TNO Voeding
Source:Food and Chemical Toxicology, 11, 42, 1885-1891
Identifier: 238082
doi: doi:10.1016/j.fct.2004.07.009
Keywords: Health · Physiological Sciences · Arylamines · CAS No.: 106-50-3 · Hair dyes · Human volunteers · N-acetyltransferase 2 · Para-phenylenediamine · Skin metabolism · arylamine acetyltransferase · carbon 14 · glucuronic acid · hair dye · phenylenediamine · acetylation · adult · aerobic metabolism · article · genotype · human · male · metabolism · metabolite · molecular weight · normal human · radioactivity · urinalysis · urine level · Absorption · Acetylation · Administration, Topical · Adolescent · Adult · Arylamine N-Acetyltransferase · Carbon Radioisotopes · Genetic Predisposition to Disease · Genotype · Hair Dyes · Humans · Male · Phenylenediamines · Pilot Projects · Urinary Bladder Neoplasms · Mammalia


In the organism of mammals, important detoxification pathways of arylamines are catalysed by N-acetyltransferase 2 (NAT2). A recent case-control epidemiology study suggested that human NAT2 slow acetylators exposed to oxidative hair dyes may be at greater risk to develop bladder cancer. We therefore profiled urinary [14C]-metabolites and NAT2 genotype in eight human subjects following treatment with a dark-shade oxidative hair dye containing [14C]-para-phenylenediamine (PPD). Genotyping identified three subjects as slow, and five subjects as intermediate NAT2 acetylators. Within 24 h after treatment, the study subjects excreted a mean total of 0.43 ± 0.24% of the applied [14C] in the urine, where five different metabolites were found. The major urinary metabolites were concluded to be N-mono-acetylated and N,N′-diacetylated PPD. They were present in all urine samples and amounted to 80-95% of the total urinary [14C]. Another metabolite, possibly a glucuronic acid conjugate, was found in 6/8 urine samples at 5-13% of the total urinary [14C]. All metabolites appeared to be related to PPD, no evidence of the presence of high-molecular weight dye-intermediates or corresponding metabolites was found. The metabolite profile in the study subjects showed no significant differences between the NAT2 intermediate and NAT2 slow acetylator subgroups. Urine of NAT2 slow acetylators contained N-mono-acetylated-PPD at 42.2 ± 10.2% and N,N′-di- acetylated-PPD at 54.1 ± 7.6% of total urinary radioactivity, while the corresponding values of intermediate acetylators were 46.0 ± 8.9% and 45.7 ± 9.9%, respectively. Overall, our results suggest that the human acetylation rate of PPD after topical application is independent of the NAT2 genotype status, most likely due to metabolism by epidermal NAT1 prior to systemic absorption. © 2004 Elsevier Ltd. All rights reserved.