Comparison of Pathologic Features in Experimental Hyperphosphatasemic Conditions in Beagle Dogs Treated with α-Naphthylisothiocyanate and Phenobarbital

Abstract

The present study was designed to clarify the pathologic features of hyperphosphatasemic conditions in association with drug metabolizing enzyme (DME) induction and cholestatic condition in dogs. Two (2) model compounds were selected; α-naphthylisothiocyanate (ANIT) and phenobarbital (PB). Groups of beagle dogs were orally given ANIT at 30 mg/kg or PB at escalating dose of 20 to 60 mg/kg for 3 weeks and subjected to in-life and postmortem examinations. Determination of hepatic DME and alkaline phosphatase (ALP) activity in liver tissue fractions as well as isoenzyme analysis of serum ALP were performed. Differences between the ANIT and PB groups were: (1) the serum enzyme profile in the ANIT group was characterized by remarkably elevated activity in leakage enzymes (ALT and AST) and ALP accompanied by a remarkable increase in plasma total bilirubin concentration and remarkable inhibition of ICG clearance, (2) the only noticeable finding in the serum enzyme profile in the PB group was remarkable elevation of ALP activity, and (3) microsomal P-450 content decreased in the ANIT group and increased in the PB group. Activities of aminopyrine demethylase and aniline hydroxylase shifted together with the change in microsomal P-450 content in the PB group, and (4) degenerative changes in the biliary system and liver cells were characteristic in the ANIT group and hyperplasia of the smooth surfaced endoplasmic reticulum was prominent in the PB group. The reported hyperphosphatasemia recorded in the PB-treated dogs has to be dealt with separately from the toxicologically significant changes seen in ANIT-treated dogs, since the source of ALP differed between the two conditions.