Paracetamol, 3-monoalkyl- and 3,5-dialkyl-substituted derivatives. Antioxidant activity and relationship between lipid peroxidation and cytotoxicity.
The analgesic drug paracetamol is known to cause lipid peroxidation and hepatotoxicity after overdosage. In this paper, the relationship between lipid peroxidation and toxicity in freshly isolated hepatocytes was studied using paracetamol and three 3-monoalkyl-substituted derivatives of paracetamol. Paracetamol was found to induce both toxicity and lipid peroxidation in the hepatocytes. 3-Monoalkyl substitution of paracetamol (R = CH3, C2H5 and iso-C3H7) did not influence its cytotoxicity but, in contrast, inhibited the lipid peroxidation. This effect may be caused by the antioxidant activity of the substituted derivatives. Apart from 3-monoalkyl substitution, 3,5-dialkyl substitution of paracetamol was also found to potentiate the antioxidant activity of paracetamol. The antioxidant activity of paracetamol and its alkyl derivatives was found to be highly correlated to their lipophilicity.
van de Straat
R
R
Department of Pharmacochemistry, Molecular Toxicology, Free University, Amsterdam, The Netherlands.
Bijloo
G J
GJ
Vermeulen
N P
NP
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013329:Structure-Activity Relationship
D000975:Antioxidants; D008054:Lipid Peroxides; D000082:Acetaminophen