METABOLISM AND CYTOTOXICITY OF CHLORPROPHAM (CIPC) AND ITS ESSENTIAL METABOLITES IN ISOLATED RAT HEPATOCYTES DURING A PARTIAL INHIBITION OFSULFATION AND GLUCURONIDATION REACTIONS - A COMPARATIVE-STUDY

The changes in metabolism and cytotoxicity of chlorpropham (CIPC) and its major metabolites, 4-hydroxychlorpropham (4-OH CIPC), 3-chloroanil ine, and 3-chloroacetanilide were investigated in isolated rat hepatoc yte suspensions after a partial inhibition of sulphation and glucuroni dation and the two reactions combined in an attempt to assess the part of each of them in the enhanced CIPC toxicity observed in vivo after D-galactosamine treatment. With sulphation and glucuronidation effecti ve, CIPC has a cytolytic effect and reduces intracellular ATP and K+ l evel while 4-OH CTPC has a weak cytolytic effect but modifies ATP and Kf level in a greater extent than CIPC. Inhibition of sulphation does not affect the cytotoxicity of CIPC or 4-OH CIPC because there is a co mpensatory increase in the amount of 4-OH CIPC glucuronide formed and the level of free 4-OH CIPC always remain low. In contrast, when incub ations are carried out with either CIPC or 4-OH CIPC, the presence of D-galactosamine leads to a decrease of glucuronide and sulphate conjug ates accompanied, respectively, by a 3.6-fold and 6.9-fold increase of the free 4-OH CIPC level in the culture medium. This alteration of th e metabolism is followed by a marked reduction of ATP synthesis with a concomitant modification of cell permeability. The cytolytic effect i s due to CIPC itself, whereas the effect on energy supply was attribut ed to free 4-OH CIPC. The results demonstrate a combined effect of fre e 4-OH CIPC and D-galactosamine on intracellular ATP level that could account for the partial inhibition of sulphation. This change in the C IPC metabolism could explain the increased CTPC toxicity observed in v ivo after D-galactosamine pretreatment.