Male Fischer 344 rats were given a single dose of 0.03-30 mg/kg of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), the radioactivity in urine and feces was determined over 48 h, and the major metabolites were identified and quantified. Dose had little effect on the profile of metabolites in the urine but did influence the profile in the feces. PhIP was more efficiently metabolized at higher doses. In addition, rats were pretreated with Aroclor 1254 (PCB), 3-methylcholanthrene (MC), phenobarbital (PB), PhIP and corn oil prior to a single dose of [14C]PhIP, and compared with a control group receiving [14C]PhIP only. The major metabolites in the urine and feces were quantitated for each group, as well as PhIP binding to serum proteins, hemoglobin and selected tissues. Pretreatment with MC and PCB resulted in an increase in the amount of 4'-hydroxylation of PhIP and a decrease in the amount of N-hydroxylated metabolites in the urine. Pretreatment with PB resulted in an increase in the amount of N-hydroxylated metabolites, but a decrease in 4'-hydroxylation. Pretreatment with either MC or PCB resulted in an increase in PhIP binding to the liver and kidney, while reducing the binding in other tissues. Animals pretreated with PhIP showed few significant differences from the untreated group, while pretreatment with PB in general resulted in a decrease of PhIP binding in tissues.
Changes in the isozymes of pepsinogen (Pg) separated from the glandular stomachs of rats were studied by polyacrylamide gel electrophoresis during carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), from the beginning of MNNG administration to 3 months after the end of its 7-month regimen. In 13 of 25 rats killed successively, one (Pg 1) of the three pepsinogen isozymes (Pg 1, 3, 4) normally present in the pyloric mucosa had decreased or disappeared. It decreas was observed from 1 week after the beginning of MNNG treatment to at least 3 months after the end of the 7-month MNNG administration. Remarkable histopathologic changes were found from 8 months after MNNG was given, and rats showing such unusual histopathologic alterations also had changes in their pepsinogen isozyme pattern. In 4 of 27 rats, two (Pg 1, 2) of the four isozymes of pepsinogen (Pg 1-4) in the fundic mucosa decreased or disappeared from 3 months after the beginning of MNNG treatment to at least 2 months after the end of its 7-month administration. Histopathologic changes induced by MNNG were not as remarkable in the fundic mucosa as in the pyloric mucosa.
The activating mutations of all three ras genes in rat Zymbal's gland tumors induced by a food mutagen, 2-amino-3-methylimidazo[4,5- f]quinoline (IQ) were analyzed. DNA fragments of the Ha-ras, Ki-ras and N-ras oncogenes were amplified from formalin-fixed and paraffin-embedded tissues by the polymerase chain reaction (PCR) and analyzed for activating mutations involving codons 12, 13 and 61 by oligonucleotide differential hybridization. All nine Zymbal's gland tumors examined, including three papillomas, were found to contain either an Ha-ras or Ki-ras mutation. These mutations were located in either codon 13 or 61 of Ha-ras, and in either codon 12 or 13 of Ki-ras. Of the nine mutations, three were G-->T, three were G-->C, two were G-->A and one was A-->T. Of the nine mutations, eight occurred at guanine bases and seven were transversions. There was no correlation between the types of mutations and the histological types of the tumors. These results suggest that ras gene activation is an important early event in the tumorigenesis induced by IQ in rat Zymbal's gland and that mutations at guanine bases are frequent, though the locations and types of the mutations are not highly specific.
Electron microphotographs showed that pancreatic acinar cells contain many dense zymogen granules in the fetal stage (day 21 of gestation), both dense and less dense granules in the infant stage (day 10 after birth) and again only dense granules in the adult stage. Injection of dexamethasone in the infant stage greatly increased the number of dense granules, and slightly increased the total number of granules, whereas its injection in the weanling stage (day 24 after birth) did not increase the total number of zymogen granules or their density. Parotid acinar cells contain many zymogen granules of low density in the weanling stage (day 24 after birth), and granules of low density with dense spots in the adult stage. Injection of dexamethasone in the weanling stage increased the number of adult-type zymogen granules, but did not increase the total number of granules. The developmental change in amylase activity was parallel with the change in the high-density areas in zymogen granules, and the latter seemed to be influenced by the serum glucocorticoid level.
The carcinogenicity of a food additive, 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (trade name, AF-2), was studied. A diet containing AF-2 at a rate of 0.25% was administered to male golden hamsters and male ddY mice. The hamsters developed squamous cell carcinomas in the forestomach after the 49th day from the start of administration. In mice fed a AF-2 diet for 308 days, squamous cell carcinoma was observed in the forestomach after the 381th day from the start of the experiment; in some cases the carcinoma metastasized to the lung and liver.
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