Keizo Furuya

An enhancing effect of the antihistaminic drug methapyrilene on rat liver carcinogenesis by previously administered N-2-fluorenylacetamide.

The effect on hepatocarcinogenesis of sequential administration of the antihistaminic drug methapyrilene (MP) or the typical liver tumor promoter, phenobarbital (PB), each given after the genotoxic liver carcinogen, N-2-fluorenylacetamide (FAA) was studied. An initial exposure to 0.02% of FAA in the diet for 8 weeks was used to produce hepatocellular altered foci. Rats maintained for an additional 24 weeks on basal diet developed a low incidence of liver neoplasms. MP at 500 and 1000 ppm in the diet for 24 weeks after FAA increased the frequency of altered foci at early stages and liver neoplasms later, as did PB. Neither MP nor PB alone produced neoplasms, but MP alone produced a significant incidence of altered foci. Therefore, the results provide evidence for a promoting action of MP, but additional effects may be involved in its carcinogenicity.

Absence of a promoting or sequential syncarcinogenic effect in rat liver by the carcinogenic hypolipidemic drug nafenopin given after N-2-fluorenylacetamide

The hypolipidemic agent nafenopin, (NF), has been reported to be carcinogenic to rat liver. To determine whether nafenopin exerts a promoting or syncarcinogenic effect in rat liver, its effect on liver carcinogenesis induced by N-2-fluorenylacetamide (FAA) was studied. In two separate experiments, male F344 rats were fed 0.02% FAA for either 10 or 8 weeks to induce preneoplastic liver lesions. Following a recovery period of 1 week, rats were given 0.01 or 0.02% NF in the diet for 23 weeks in one experiment and 0.05 or 0.1% for 24 weeks in the other. The final incidence of neoplasms, and their numbers, size distribution, and degrees of differentiation were not significantly different in groups given NF after FAA compared to those maintained on a basal diet after FAA. In the group treated with the highest dose level of NF following FAA, however, there was a decrease in the number of grossly visible small neoplasms. In contrast, the liver neoplasm promoter phenobarbital increased the multiplicity, although not the incidence, of liver neoplasms when given after FAA. Thus, four different dose levels of NF showed no promoting or syncarcinogenic effect on FAA-induced hepatocarcinogenesis.

Neoplastic conversion in rat liver by the antihistamine methapyrilene demonstrated by a sequential syncarcinogenic effect with N-2-fluorenylacetamide

A study was performed to determine whether the enhancing effect of the antihistamine methapyrilene (MP) in rat liver carcinogenesis represents promotion or syncarcinogenesis . The effect on hepatocarcinogenicity induced by N-2-fluorenylacetamide (FAA) of sequential administration of MP given either before or after FAA was studied in comparison with diethylnitrosamine (DEN) also given either before or after FAA. MP in either sequence with FAA enhanced liver carcinogenicity as did DEN. Moreover, MP by itself induced liver altered foci, albeit at a high dose for a prolonged interval. A single liver neoplasm occurred with exposure to MP alone. These findings suggest that MP produces neoplastic conversion of liver cells which can be summated with the genotoxic effect of FAA to produce syncarcinogenesis .

Effect of DNA synthesis on induction of preneoplastic and neoplastic lesions in rat liver by a single dose of methylazoxymethanol acetate

A single intravenous injection of methylazoxymethanol (MAM) acetate in doses of either 20 or 35 mg/kg body weight to male Sprague-Dawley rats induced altered liver cell foci and later, liver neoplasms in a dose related manner. Sequential observations in the rats given 35 mg/kg and thereafter fed an iron-loading diet revealed that the number of iron-excluding foci/cm2 increased with time. Partial hepatectomy (PH) before the high dose of MAM acetate resulted in 100% lethality while hepatectomy before the low dose carcinogen exposure lead to a higher incidence of neoplasms than in rats that received carcinogen alone. PH after either high or low dose carcinogen exposure did not result in a greater occurrence of liver neoplasms.

The effect of chronic ethanol consumption on the tumorigenicity of N-nitrosopyrrolidine in male Syrian golden hamsters

The effect of oral administration of ethanol on the tumorigenicity of N-nitrosopyrrolidine (NPYR) in chow-fed male Syrian golden hamsters has been investigated. Groups of hamsters were given tap water, 7.4% ethanol or 18.5% ethanol-water mixtures 4 weeks prior to and throughout the carcinogen administration period. A total dose of 1 mmol NPYR was administered by intraperitoneal injection to both tap water and ethanol-consuming animals over a 25-week period. Twenty-four hours after the last injection, ethanol-consuming animals were returned to tap water. In control animals treated with NPYR we observed 3/26 animals with tracheal papillomas, and 6/26 animals with hepatic neoplastic nodules. In animals receiving 7.4% ethanol-water mixtures, we observed 6/26 tracheal papillomas, and 17/26 hepatic neoplastic nodules. Similar results were observed in animals receiving 18.5% ethanol. These data indicate that chronic administration of ethanol to chow-fed hamsters increases the incidence of hepatic neoplastic nodules although no differences in the two levels of ethanol were observed.

Abnormalities in liver iron accumulation during N-2-fluorenylacetamide hepatocarcinogenesis that are dependent or independent of continued carcinogen action.

The characteristics of liver iron accumulation were studied during N-2-fluorenylacetamide (FAA)-induced hepatocarcinogenesis in rats. After injection of iron-dextran in control rats, hepatocytes accumulated stainable iron evenly throughout hepatic lobules. During the feeding of FAA, iron accumulation was reduced in the midzonal and centrilobular regions. After FAA removal, hepatocytes in these regions again accumulated high amounts of iron. Hepatocellular altered foci induced by FAA displayed rather uniform (> 94%) iron-exclusion during FAA feeding. After FAA removal, however, iron-exclusion was lost in a fraction of the foci, while others (40-64%) remained resistant to iron accumulation. A large majority of liver neoplasms (> 93%) displayed resistance to cellular iron accumulation both during FAA feeding and after removal of FAA. Thus, iron-exclusion by liver neoplasms is carcinogen-independent and irreversible, in contrast with that of normal hepatocytes which is completely carcinogen-dependent and reversible. Altered foci appear to represent two populations: one is characterized by reversible iron-exclusion whereas the other, like neoplasms, possesses permanent iron-exclusion.

Iron exclusion by proliferative foci and neoplastic lesions induced by 7,12-dimethylbenz (a) anthracene in the rat adrenal cortex

SummaryProliferative and neoplastic adrenal cortical lesions were produced in female Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene. These lesions were studied for their ability to store histochemically demonstrable cellular iron compared with normal adrenocortical cells following iron loading by subcutaneous injection of iron-dextran. Stainable iron was excluded, under conditions in which normal cortical cells were heavily loaded with iron, in three histological types of adrenalcortical lesions; eosinophilic and basophilic proliferative foci; adenomas and lesions transitional between foci and tumours. The property of iron exclusion may be useful in studying neoplastic development in the adrenal gland.