Background and aims: Acetaminophen (APAP) or paracetamol is a hepatotoxic d
rug through mechanisms involving oxidative stress. To know whether mammalia
n cells possess inducible pathways for antioxidant defense, we have to stud
y the relationship between heme metabolism and oxidative stress. Methods: f
asted female Wistar rats received a single injection of APAP (3.3 mmol kg(-
1) body weight) and then were killed at different times. Heme oxygenase-1 (
HO), delta -aminolevulinic acid (ALA) synthase, ALA dehydratase, and porpho
bilinogenase activities, lipid peroxidation, GSH, catalase and glutathione
peroxidase, were measured in liver homogenates. The antioxidant properties
of bilirubin and S-adenosyl-L-methionine were also evaluated. Results: APAP
increased lipid peroxidation (115% +/- 6; S.E.M., n = 12 over control valu
es) 1 h after treatment. GSH reached a minimum at 3 h (38% +/- 5) increasin
g thereafter. At the same time antioxidant enzymes reached minimum values (
catalase, 5.6 +/- 0.4 pmol mg-protein, glutathione peroxidase, 0.101 +/- 0.
006 U mg(-1) protein). HO induction was observed 6 h after treatment reachi
ng a maximum value of 2.56 +/- 0.12 U mg(-1) protein 15 h after injection.
ALA synthase (ALA-S) induction occurred after enhancement of HO, reaching a
maximum at 18 h (three-fold the control). ALA dehydratase activity was fir
st inhibited (31 +/- 3%) showing a profile similar to that of GSH, while po
rphobilinogenase activity was not modified along the whole period of the as
say. Administration of bilirubin (5 mu mol kg(-1) body weight) or S-adenosy
l L-methionine (46 mu mol kg(-1) body weight) 2 h before APAP treatment ent
irely prevented the increase in malondialdehyde (MDA) content, the decrease
in GSH levels as well as HO and ALA-S induction. Conclusion: This study sh
ows that oxidative stress produced by APAP leads to increase in ALA-S and H
O activities, indicating that toxic doses of APAP affect both heme biosynth
esis and degradation. (C) 2000 Elsevier Science Ltd. All rights reserved.