Investigation of the cytotoxicity produced by generation of short-lived reactive metabolites in vitro: A study with paracetamol.
A V79 cell incubation, incorporating rat or hamster liver 9000 g supernatant (S-9) or microsomal fraction and used previously to detect the toxicity of reactive metabolites of cyclophosphamide and bromobenzene, has been used to examine the toxicity of short-lived reactive metabolites of paracetamol. Cytotoxicity was observed in the absence of an activating system and did not increase when an activating system was included in the incubation, even when this was derived from the livers of hamsters treated with beta-naphthoflavone (to increase the activity of the cytochrome P-450 form responsible for paracetamol activation) and diethyl maleate (to deplete protective glutathione stores). The failure to detect metabolism-mediated cytotoxicity of paracetamol in this assay system may be related to the high reactivity of the toxic metabolite. This, in turn, suggests that other systems, based on activation within target cells or on the detection of an endpoint closer to the activation event, are required for the in vitro detection of short-lived cytotoxic metabolites.
Horner
S A
SA
Department of Human Morphology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, England.
Zucco
F
F
Fry
J R
JR
Clothier
R H
RH
Balls
M
M