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AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver

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Abstract

N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so far, AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in rat and human, the toxicity of APAP and AMAP was tested ex vivo in precision-cut liver slices (PCLS) of mouse, rat and human. Based on ATP content and histomorphology, APAP was more toxic in mouse than in rat and human PCLS. Surprisingly, although AMAP showed a much lower toxicity than APAP in mouse PCLS, AMAP was equally toxic as or even more toxic than APAP at all concentrations tested in both rat and human PCLS. The profile of proteins released into the medium of AMAP-treated rat PCLS was similar to that of APAP, whereas in the medium of mouse PCLS, it was similar to the control. Metabolite profiling indicated that mouse PCLS produced the highest amount of glutathione conjugate of APAP, while no glutathione conjugate of AMAP was detected in all three species. Mouse also produced ten times more hydroquinone metabolites of AMAP, the assumed proximate reactive metabolites, than rat or human. In conclusion, AMAP is toxic in rat and human liver and cannot be used as non-toxic isomer of APAP. The marked species differences in APAP and AMAP toxicity and metabolism underline the importance of using human tissues for better prediction of toxicity in man.

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Acknowledgments

This work was supported by Dutch Top Institute Pharma, project D3-201-1 (Towards novel translational safety biomarkers for adverse drug toxicity). The authors would like to thank Dr. Inge de Graaf for making the microscopic images and scoring all the histomorphology data. We also thank Coby Laarakkers and Dr. Roos Masereeuw for providing valuable assistance and discussion in generating the protein profiling data. The authors are very grateful to Prof. Robert Porte (Dept. Surgery, UMCG) for providing human liver samples and Dr.ir. Arjen Lommen for providing APAP-glucuronide, APAP-sulfate and APAP-GSH standard solutions. Dr. Kevin Augustijn is also thanked for his help in managing this collaborative project.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    Mackenzie Hadi & Geny M. M. Groothuis

  2. Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Sanja Dragovic & Jan N. M. Commandeur

  3. Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Rachel van Swelm & Frans G. M. Russel

  4. Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Bram Herpers & Bob van de Water

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  1. Mackenzie Hadi
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Correspondence to Mackenzie Hadi.

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Hadi, M., Dragovic, S., van Swelm, R. et al. AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver. Arch Toxicol 87, 155–165 (2013). https://doi.org/10.1007/s00204-012-0924-1

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