Initiation of free radical reactions and hepatotoxicity in rats poisoned with carbon tetrachloride or bromotrichloromethane

Abstract

Morphological studies [1, 2] have shown that bromotrichloromethane behaves as a more dangerous hepatotoxin than carbon tetrachloride.The present investigation extends those preliminary findings and offers new biochemical evidences for the hypothesis suggested by the relationship between the toxicity and the level of the bond dissociation energy. The electron paramagnetic resonance signal and the UVspectrum of double bond shifting in microsomal lipids show that CBrCI3 administration induces a more rapid and extensive free radical reaction in liver than CCI 4. More severe pathological phenomena are coincident with a more profound pro-oxidant effect of bromotrichloromethane. In fact, 0.26 mmol of CBrC13 prove lethal after having caused massive fatty liver and necrosis, while an equimolecular amount of CCI~ induces a lower and transient hepatic triglyceride accumulation and necrosis. Under the same experimental conditions, the lethal dose of carbon tetrachloride is twenty times higher (5.16 mmol per 100 g body weight). CCl4-poisoned rats develop a remarkable dissociation of liver polysomes. In animals given an equivalent dose of CBrCI~ these damages occur within a shorter lag period and are more severe. Moreover, the recovery takes place much later than when carbon tetrachloride is used.A clear inverse relationship exists between the level of bond dissociation energy of these two halogenoalkanes (respectively, 49 and 68 kcal tool -1, for CBrC13 and CCIa) and their potency to stimulate free radical reactions and to produce liver injury.

Biochemical studies on the metabolic activation of halogenated alkanes.

“…In the latter series, where CC13' can be the common free radical product, the relative signal intensity of the PBN spin adducts is in good agreement with previous results on the ability to induce microsomal lipid peroxidation (63) and the hepatotoxicity of these halomethanes (35).…”

Hepatotoxicity and lethality of halomethanes in Mongolian gerbils pretreated with chlordecone, phenobarbital or mirex

“…The 48 h LDs0 value for CBrCI3 reported here indicates that this compound is 4-fold more toxic than CC14 to gerbils, even though the gerbils are already very sensitive to CC14 toxicity. The descending order of the bond dissociation energy for CHCI3>> CC14>> CBrCI3 (Burdino et al 1973), corresponds well with the descending order of their 48 h LDs0 values (Table 1). This observation is consistent with the commonly accepted inverse relationship between the bond dissociation energy of a series of halomethanes and their potency to initiate free-radical reactions, and to produce liver injury (Recknagel and Glende 1977;Reynolds and Moslen 1980).…”

Histological Evidence for Dissociation of Lipid Peroxidation and Cell Necrosis in Bromotrichloromethane Hepatotoxicity in the Perfused Rat liver.

“…The sensitivity of the staining method, therefore, appears low com pared with the biochemical method, and this is the reason why we used CBrC13, which has greater peroxidative and necrogenic activity than CC14 (3,18), and the reason why we used phenobarbital-pretreated rats, in which halogenomethane hepatotoxicity is known to be enhanced (19).…”

“…Therefore, if lipid peroxidation is a prereq uisite for the development of necrosis, it should at least occur in the centrilobular zones and precede necrosis, although occurrence of lipid peroxidation and cell necrosis in the same area does not always prove a definite causal relationship. Biochemical methods have clearly characterized lipid peroxidation as a very early event in halogenomethane hepato toxicity (3,8,9), whereas the lobular localiza tion of lipid peroxidation is still unclear. On this point, Taper et al (10) developed a his tochemical method for determining the topography of cellular aldehydes in the liver lobules by the Schiff reaction, i.e., using fuch sin staining of cellular aldehydes.…”