Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.
Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4- to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.
Basile
A S
AS
Laboratory of Neuroscience, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Pannell
L
L
Jaouni
T
T
Gammal
S H
SH
Fales
H M
HM
Jones
E A
EA
Skolnick
P
P
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000378:metabolism; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013853:Thioacetamide; D014020:Tissue Extracts / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D014020:Tissue Extracts; D013853:Thioacetamide; D003975:Diazepam