Hepatotoxicity of menadione predominates in oxygen-rich zones of the liver lobule.
This study was designed to investigate the mechanism of zone-specific hepatotoxicity due to menadione. Infusion of menadione (64-1000 microM) into perfused livers from fasted rats caused a concentration-dependent increase in O2 uptake. During perfusion in the anterograde direction, menadione (1 mM) increased O2 uptake from 115 +/- 11 to 142 +/- 10 mumol/g/hr within 30 min, followed by a decrease to 92 +/- 11 mumol/g/hr over the next 30 min. Trypan blue was taken up by 90% of cells in periportal regions reflecting irreversible cell death, whereas cells in pericentral areas were not damaged. When the hepatic O2 gradient was reversed by perfusing in the retrograde direction, menadione increased O2 uptake initially from 114 +/- 11 to 132 +/- 14 mumol/g/hr, followed by a decline to 51 +/- 12 mumol/g/hr, qualitatively similar to data obtained from perfusions in the natural, anterograde direction. During perfusions in the retrograde direction, however, 95% of cells in pericentral regions were stained with trypan blue whereas those in periportal areas were spared. O2 uptake in specific zones of the liver lobule was then measured with miniature O2 electrodes. When menadione was infused during anterograde perfusions, O2 uptake increased in O2-rich periportal areas from 128 +/- 6 to 156 +/- 12 mumol/g/hr, but was not altered in pericentral regions. Conversely, during perfusions in the retrograde direction, menadione did not affect O2 uptake in periportal areas, but stimulated uptake in O2-rich pericentral regions from 120 +/- 4 to 150 +/- 14 mumol/g/hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Badr
M Z
MZ
Department of Pharmacology, University of North Carolina at Chapel Hill.
Ganey
P E
PE
Yoshihara
H
H
Kauffman
F C
FC
Thurman
R G
RG
D000818:Animals; D005260:Female; D005609:Free Radicals; D005978:Glutathione / Q000502:physiology; D008099:Liver / Q000187:drug effects*; D010100:Oxygen / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000633:toxicity*
D005609:Free Radicals; D014812:Vitamin K; D005978:Glutathione; D010100:Oxygen