Effect of “Drugs for Liver Disease” on Hepatotoxic Action of Carbon Tetrachloride

Abstract

Abstract-In order to clarify the action of drugs for liver disease, the effect of proto porphyrin (PP) on CC1,-induced liver injury was studied. Attention was given to the levels of lysosomal enzymes, some components of the liver, and inhibition of enzymes and lysis of lysosomal membranes by lipid peroxides. Administration of PP to CC], poisoned rats was found to prevent the decrease in lysosomal lipolytic enzyme level in the liver, but not in other enzyme levels tested. The inhibition of lipolytic en zyme by CCl, administered may be partially involved in lipid accumulation in the liver. A dose of PP administered to CCI,-poisoned rats for 8 days depressed the neu tral lipid content in the liver nearly to the control value. Methyl linoleate hydro peroxide (hydroperoxide) at a lower concentration of 10-1% inhibited the lipolytic enzyme activity by 30'//0 and in concentrations ranging from 10-' to 10-1% inhibited N-glucuronidase activity. Addition of PP to the medium containing 10-s to 10_5 hydroperoxide and a-tocopherol reduced the enzyme inhibition further than in the absence of PP. The hydroperoxide in concentrations varying from 10-1 to 10-3 caused a partial lysis of liver lysosomal membranes, but addition of PP slightly re duced the damage by the hydroperoxide in concentrations lower than 10-1%.The existence of lysosomes containing a variety of acid hydrolases in rat liver, first recognized in 1955 by de Duve et al. (1), drew attention to the possibility that the segrega tion of such hydrolytic enzymes might be a mechanism for control and restriction of auto lysis. There is a fair amount of evidence that lysosomes are concerned with the process of intracellular digestion and are involved in various physiological and pathological pheno mena of autolysis and necrosis (2). Much biochemical work has been done in attempts to elucidate the pathogenesis of the liver injury produced by CC14 (3-5). It is known that administration of a suitable dose of CCl4 to rats results in a severe centrilobular type of necrosis and fatty degeneration of the liver (6), profound metabolic disturbances such as changes in the hepatic level of enzymes (7) and defective protein synthesis in the injured liver (8, 9). Dianzani showed that after CC14 poisoning, there was evidence for uncoupl ing of oxidative phosphorylation, loss of mitochondrial pyridine nucleotides, and lowering of the liver content of adenosine 5'-triphosphate (5, 10). It is also shown that lysosomes are involved in the later scavenging process of liver injury (11).At present, drugs such as protoporphyrin (PP), are clinically used for liver diseases.However, little is known of the effects of these drugs on the lysosomal enzymes of an in jured liver. To clarify their action, the effects of PP on the decreased lysosomal enzyme

Effect of “Drugs for Liver Disease” on Hepatotoxic Action of Carbon Tetrachloride

“…4). This also suggests that the protecting effect plays an important role in depressing the fat accumulated in CCI4 poisoning, as we reported (23). On the other hand, administration of PC to CC14-poisoned rats hardly increased the microsomal drug metabolizing enzyme activities.…”

“…The overall mechanism of the action of drugs for liver disease, however, has not yet been made clear. The effect of PP on lysosomal enzymes and some components of injured liver has already been reported by the present authors (23). To clarify the ac tion of these drugs on microsomal drug-metabolizing enzyme activities and the components, during liver injury, some experiments were carried out in vivo and in vitro.…”

“…A possible explanation for the stimulating effect may be: (1) PP increases the synthesis or protects against the decomposition of P-450 after the incorpora tion of PP into liver microsomal fractions (42), as suggested by the data obtained with a single daily dose of PP to normal rats (Table 3); and (2) a protecting effect of PP against the inhibition of the enzymes by lipid peroxides owing to an increase in the protecting ef fect of endogenous antioxidant materials, as described in our previous paper (23). The decreased metabolic rate of the other xenobiotics (and some endogenous compounds) may therefore return to normal levels earlier with administration of PP.…”

“…The lipolytic enzyme activity was assayed by the method described in a previous paper (23), except that 5 % triolein emulsion was used instead of tributyrin substrate. Difference spectrophotometey: Difference spectra were measured in a Shimadzu MPS 50L spectrophotometer, using two sets of matched quartz cuvettes of 1.0 and 0.5 cm-optical path.…”