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Investigations on detoxification mechanisms of novel para-phenylenediamine analogues through N-acetyltransferase 1 (NAT-1).
Venkatesan, Gopalakrishnan; Lim, Zhi Chiaw; Karkhanis, Aneesh V; Neupane, Yub Raj; Dancik, Yuri; Huang, Chenyuan; Bigliardi, Paul; Pastorin, Giorgia.
Affiliation
  • Venkatesan G; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #12-02 CREATE Tower, Singapore, 138602, Singapore. gopal.venkatesan@smart.mit.edu.
  • Lim ZC; Department of Pharmacy, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, Singapore, 117544, Singapore. gopal.venkatesan@smart.mit.edu.
  • Karkhanis AV; Department of Chemistry, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 3, Singapore, 117544, Singapore.
  • Neupane YR; Skin Research Institute of Singapore, A*STAR, 8A Biomedical Grove, Immunos Building, Singapore, 138665, Singapore.
  • Dancik Y; Department of Pharmacy, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, Singapore, 117544, Singapore.
  • Huang C; Le Studium Loire Valley Institute of Advanced Studies, Orléans, France.
  • Bigliardi P; Université de Tours, Faculté de Pharmacie, EA 6295 Nanomédicaments et Nanosondes, 31 avenue Monge, 37200, Tours, France.
  • Pastorin G; Simcyp Division, Certara UK Ltd., Level 2-Acero, 1 Concourse Way, Sheffield, S1 2B1, UK.
Arch Toxicol ; 96(1): 153-165, 2022 01.
Article in En | MEDLINE | ID: mdl-34773126
ABSTRACT
Para-phenylenediamine (PPD) is one of the most used chemicals in oxidative hair dyes. However, its use has been associated with adverse effects on health, including contact dermatitis and other systemic toxicities. Novel PPD derivatives have been proposed as a safer replacement for PPD. This can be achieved if these molecules minimally permeate the skin and/or are easily metabolised by enzymes in the skin (e.g., N-acetyltransferase-1 (NAT-1)) into innocuous compounds before gaining systemic entry. This study investigated the detoxification pathway mediated by NAT-1 enzymes on 6 synthesized PPD analogues (namely, P1-P6) with different chemical properties, to study the role of functional groups on detoxification mechanisms in HaCaT skin cells. These compounds were carefully designed with different chemical properties (whereby the ortho position of PPD was substituted by nucleophile and electrophile groups to promote N-acetylation reactions, metabolism and clearance). Compounds P2-P4 N-acetylated at 54-49 nmol/mg/min, which is 1.6 times higher than N-acetylation of PPD, upregulated NAT-1 activity from 8-7% at 50 µM to 22-11% at 100 µM and showed 4 times higher rate of elimination (k equal to 0.141 ± 0.016-0.124 ± 0.01 h-1) and 3 times faster rate of clearance (0.172 ± 0.007-0.158 ± 0.005 h-1mgprotein-1) than PPD (0.0316 ± 0.0019 h-1, 0.0576 ± 0.003 h-1mg protein-1, respectively). The data suggest that nucleophile substituted compounds detoxify at a faster rate than PPD. Our metabolic and detoxification mechanistic studies revealed significantly higher rates of N-acetylation, NAT-1 activity and higher detoxification of P2-P4 in keratinocytes, suggesting the importance of nucleophilic groups at the ortho position in PPD to reduce toxicity of aniline-based dyes on human skin cells.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dermatitis, Allergic Contact / Hair Dyes Limits: Humans Language: En Journal: Arch Toxicol Year: 2022 Type: Article Affiliation country: Singapore

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dermatitis, Allergic Contact / Hair Dyes Limits: Humans Language: En Journal: Arch Toxicol Year: 2022 Type: Article Affiliation country: Singapore