The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low doses of acetaminophen converted to the mercapturic acid metabolite was highest in the most susceptible species (hamsters, mice), and lowest in the more resistant species (rat). Pretreatment regimens known to potentiate the hepatotoxicity increased mercapturic acid formation whereas treatments which protect from liver damage decreased mercapturic acid formation. The data suggest that the activity of the mercapturic acid-forming pathway in vivo reflects the activity of the hepatotoxic pathway. As the dose of acetaminophen was increased to hepatotoxic levels, the fraction of the dose excreted as the mercapturic acid decreased markedly, commensurate with the known depletion of hepatic glutathione under these conditions. It is suggested that the normal metabolic intermediate which conjugates with glutathione in the mercapturic acid pathway is also the electrophilic metabolite which in the absence of glutathione arylates hepatic macromolecules and causes cell death.

Keywords:
Acetaminophen, Glutathione, Liver necrosis, Mercapturic acid, Toxic dose threshold, Toxic metabolite
This content is only available via PDF.
© 1974 S. Karger AG, Basel
1974
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.