No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

The APC gene plays a major role in human colon carcinogenesis. We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) and 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food. Of eight PhIP-induced tumors, one tumor had two Apc mutations, two tumors had a mutation with loss of the normal allele, and one had a mutation. Two of the above five mutations were at nucleotide 1903, one at 2605, and two at 4237, all being a deletion of a guanine base at the 5'-GGGA-3' site and resulting in truncation of the APC protein. Of 13 IQ-induced tumors, 2 had anApc mutation with loss of the normal allele. The two mutations were a missense mutation (T --C) at nucleotide 1567 and a nonsense mutation (C -* T) at 2761. Alteration of the Apc gene was shown to play a more important role in PhIP-induced than in IQ-induced rat colon carcinogenesis. PhIP-induced tumors are characterized by their specific and unique mutation, which may be useful for mutational fingerprinting of human cancers.More is known about the molecular pathways of human colon carcinogenesis than about those of most other human cancers (1-3). In typical adenoma-carcinoma courses, sequential genetic alterations of the APC, Ki-ras, p53, and DCC genes have been shown. On the other hand, mutations in DNA repair enzymes have also been reported in hereditary nonpolyposis colon carcinomas (4). In spite of the demonstration of these various molecular pathways in colon cancers, there are still some colon cancers whose molecular pathways have not yet been identified, such as flat type or de novo type colon cancers, which rarely show mutation of Ki-ras (5, 6).The mutagenic heterocyclic amines (HCAs) 2-amino-imethyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) induce colon carcinomas in F344 rats (7,8). PhIP was first isolated from fried ground beef (9), and it has been found to be the most abundant HCA in various cooked meats and fish (7). IQ was first isolated from broiled fish (10), and it is present not only in cooked food but also in cigarette smoke (11). Considering the presence of PhIP and IQ in ordinary human foods, clarification of the genetic alterations in the colon carcinomas induced by these two compounds is important. We have already reported that mutations in the Ki-ras or p53 gene are not involved in colon carcinogenesis in rats induced by PhIP or IQ, and we have suggested the usefulness of these tumors to investigate molecular pathways of carcinogenesis in which mutations in Ki-ras or p53 are not involved (12,13 Clarification of the involvement of the Apc gene (rat gene nomenclature) alterations in the rat colon tumors induced by PhIP and IQ is important for determining with which type of human colon cancers these rat colon tumors share molecular pathways. For this purpose, we have recently determined the cDNA sequence of the ratApc gene...

1. The induction of phase I and II enzymes in the liver of the male F344 rat drinking 2% (w/v) solutions of green or black tea for 6 weeks was investigated. Also studied were glutathione (GSH) and cyst(e)ine in blood, liver and kidney, as well as serum cholesterol, HDL cholesterol, triglycerides, and total and free testosterone. 2. The total carbon monoxide-discernible liver P450, b5 and NADPH-cytochrome c(P450) reductase activities were similar in all groups. 3. There were significant increases in liver of rat drinking green or black tea of P4501A1, 1A2 and 2B1 activities, but no change in P4502E1 and 3A4 activities. Of the phase II enzymes, UDP-glucuronyltransferase was increased, but glutathione S-transferase was not. 4. Serum GSH was higher in the group administered black tea, but GSH and cyst(e)ine in other groups was at control levels. Serum cholesterol was lower in rat given black compared with green tea. Triglycerides had a declining trend after green and black tea exposure compared with water controls. Free and total testosterone were not affected. 5. Thus, beverages widely used by man altered host biochemistry as regards specific phase I and II enzymes in liver of rat and specific serum parameters.