Det overgripande nationella folkhalsomalet har ett tydligt fokus pa jamlikhet i halsa, nagot som ocksa avspeglas i Folkhalsomyndighetens instruktion. I denna artikel diskuteras begreppen sociala determinanter, sociala investeringar och social hallbarhet, vilka anvands i utvecklingsarbeten bade i Sverige och internationellt. Diskussionen fors utifran folkhalsans faktapremisser och vardepremisser. Vi konstaterar att begreppen inte representerar nagot nytt inom folkhalsoomradet, men att de har bidragit till okat fokus pa jamlikhet och hallbarhet. Folkhalsomyndigheten arbetar idag pa bred front med fragor rorande jamlikhet i halsa och ser behovet av analytisk utveckling gallande valet av ojamlikhetsmatt, valet av halsomatt, epidemiologisk analys och utvardering av insatser. For Folkhalsomyndigheten ar det viktigt att fakta presenteras pa ett satt som ger politiker mojlighet att fatta informerade beslut.

To analyze the influence of different levels of dietary casein on the initiation process, male Wistar rats, pair-fed on isocaloric diets containing 5, 15 or 40% casein were initiated with a single dose of aflatoxin B1, 28 days after the experimental start. From day 4 after initiation and until selection of initiated cells was started, 25 days later, rats were fed the 15% casein diet, providing an identical dietary background during the selection period. Promotion/selection of initiated cells was performed by the combined treatment with 0.02% 2-acetylaminofluorene in the 15% casein diet for 2 weeks and a two-thirds partial hepatectomy (PH) in the middle of this period. The number of enzyme-altered hepatic lesions per rat was shown to increase with increasing content of casein in the diet, both when liver sections were stained for gamma-glutamyltransferase and with immunohistochemical staining for the placental form of glutathione-S-transferase. Non-initiated rats fed the different levels of casein exhibited a very low number of foci. Livers were secured also from non-initiated rats at the same point of time as initiation was performed. Whereas no significant differences in the total microsomal content of cytochrome P450 were observed, a higher microsomal capacity to perform 16 alpha-hydroxylation of 4-androstene-3,17-dione was observed in preparations from rats fed 40% casein, when compared with rats receiving the 5% casein diet. The dietary protein content at the time of initiation did not affect the expression of the c-rasHa, c-myc or c-fos protooncogenes, either at initiation, on day 3, or at PH.

There is a falling longitudinal gradient of P-450IA1 along the length of the small intestine of rats fed a stock diet or a BNF-containing diet. In rats fed a special diet, based on purified ingredients, the gradient was abolished but could be restored by addition of betanaphthoflavone (BNF) to the diet. This indicates that the distribution of P-450IA1 in the rat small intestine is regulated by dietary components. Tape-section autoradiographic analysis showed that exposure to dietary BNF was an important determinant for the disposition of C-14-Trp-P-1. Following dietary BNF treatment, a pronounced retention of radioactivity was observed in the epithelium of the oral cavity, esophagus, forestomach and small intestine, but not in the glandular stomach. This was obvious but less striking in rats given BNF intraperitoneally, whereas no retention could be observed in the gastrointestinal tract of untreated rats.

Mutagenic and carcinogenic heterocyclic aromatic amines are formed in protein-rich food cooked under household conditions. The compounds have been shown to be activated mainly by cytochromes P-450 IA1 and IA2. In the conventional rat, these P-450 enzymes were increased in the intestinal mucosa following oral administration of fried meat at a level comparable to human consumption. No such increase was observed in germfree rats. Furthermore, the metabolic disposition of the mutagenic material differed between the germfree and the conventional animals. A different urinary pattern of mutagenic metabolites and a substantially lower fecal mutagen excretion was observed in the germfree rats. The results implies a role of the intestinal microflora in the metabolism of fried meat mutagens.

To evaluate a possible role of the intestinal microflora in the metabolism of the highly mutagenic compounds formed in fried meat, conventional and germfree male AGUS rats were fed a semi-synthetic diet containing fried meat. Changes in mutagen excretion in urine and faeces over time were studied using the Ames Salmonella assay. The faecal and urinary extracts were separated by means of high-performance liquid chromatography (HPLC), and the mutagenicity of the collected fractions was determined. Cytochrome P-450 IA (IA1 and/or IA2) were detected by the use of antibodies with the Western blot technique, and the corresponding enzyme activities were measured in microsomes from the small intestine and the liver. A quantitative as well as qualitative difference in excretion of mutagens between germfree and conventional rats was observed. The total excreted of mutagenicity was significantly higher for the conventional than for the germfree rats, as a result of a higher faecal excretion of mutagens in the conventional animals. The HPLC separations of urinary and faecal extracts showed a different mutagenic metabolite pattern between the germfree and conventional rats. An increased activity of the cytochrome P-450-dependent enzyme ethoxyresorufin-O-deethylase was observed in the small intestine of conventional rats on the fried meat diet, whereas no effect of this diet was observed in the germfree rats. Similar results were obtained in immunoblotting experiments using a P-450 IA antiserum. The present study indicates that the excretion pattern and thus also the metabolism of compounds present in fried meat are affected by the germfree status.

The effect of dietary beta-naphthoflavone (BNF) on tissue retention of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was studied in the rat. Female rats, 3 weeks old, were fed a BNF-containing diet for 3 days before being dosed orally or i.v. with 14C-labelled Trp-P-1. The rats were killed at 4, 24 or 48 h after dosage and subjected to tape-section autoradiography. The tissue localization of Trp-P-1-derived radioactivity was compared to that observed in untreated rats and in rats given BNF i.p. Ethoxyresorufin-O-deethylase (EROD) activity and mutagenicity of Trp-P-1 in the Ames test, using S9 prepared from forestomach, glandular stomach, small intestine, liver and lung, were used as in vitro assays to measure the degree of cytochrome P450IA1 and/or P450IA2 induction. Dietary BNF treatment caused a 30- to 40-fold increase in EROD activity in the small intestine, but only a 2-fold increase in the liver and the lung. These inter-organ differences were not observed after i.p. administration of BNF. The increase in mutagenicity of Trp-P-1 in the Ames test could be correlated to the increase in EROD activity. The autoradiographic data showed that the route of administration of BNF as well as of Trp-P-1 were important for the tissue localization of Trp-P-1. Dietary BNF treatment caused a pronounced retention of Trp-P-1-derived radioactivity in the epithelia of the small intestine, forestomach, oesophagus and the oral cavity, regardless of the administration route of Trp-P-1; a similar though less pronounced epithelial retention was observed after i.p. injection of BNF. A clear-cut boundary of accumulated radioactivity between the forestomach and the glandular stomach where the levels were almost non-detectable was observed in rats fed the BNF-containing diet. It is concluded that dietary inducers may be important determinants of metabolism and tissue distribution of toxic compounds.

Fried meat was included in the diet of Sprague-Dawley rats during one week. Ingested and excreted amounts of mutagenic activity were determined daily by the use of the Ames' Salmonella/mammalian microsome test on extracts of the diet, urine and feces. In addition, the effect of the fried meat on ethoxyresorufin-O-deethylase activity in the small intestine and in the liver was measured. The results were compared to those from a control group of rats receiving boiled instead of fried meat as their source of protein. The diet containing boiled meat was not mutagenic and none of the samples from the control group, neither urine nor feces, contained any mutagenicity. The activity of ethoxyresorufin-O-deethylase in the small intestine was increased by fried meat whereas this enzyme activity in the liver was unaffected. O-deethylation of ethoxyresorufin is catalyzed by cytochrome P-450 dependent enzyme(s) and induction of the enzyme activity might indicate an increased metabolicactivation of premutagens and precarcinogens in the intestine. It is not yet known whether the mutagens excreted by the animals receiving the fried meat diet represent unmetabolized dietary mutagens or are formed as a result of metabolic activation of compounds in fried food.

A procedure is presented for the isolation of subcellular fractions from small intestinal mucosal cells in the rat. The mucosal cells were detached by a scraping procedure resulting in an almost complete harvest of all types of cells as judged by light microscopy. Homogenization using a Potter-Elvehjem Teflon-glass device at high speed with ensuing sonication was found to be necessary for complete disruption of the cells. The subcellular fractions obtained after differential centrifugation--10,000g pellet, 105,000g pellet (microsomal fraction), and supernatant--were characterized with respect to different marker enzymes. The highest yield of 7-ethoxyresorufin-O-deethylase and NADPH-cytochrome c reductase activity in the microsomal fraction was achieved after resuspension and recentrifugation of the 10,000g pellet. Addition of anti-P-450 beta-naphthoflavone (BNF)-B2 antibodies to the incubation mixture resulted in almost complete inhibition of the O-deethylation of 7-ethoxyresorufin whereas addition of anti-P-450 phenobarbital (PB)-B2 had no effect. The presence of BNF-inducible isozymes was demonstrated by the Western blotting technique not only in intestinal microsomes from BNF-treated rats, but also in microsomes from untreated rats. Anti-P-450 BNF-B2 was also used in the peroxidase-antiperoxidase method for studies on the localization of cytochrome P-450. No BNF-inducible cytochrome P-450 could be detected in untreated rats, whereas BNF treatment resulted in a general staining of the whole villus.

In contrast with conventional rats, 2-acetamido-4-(chloromethyl)thiazole was not metabolized to the 4-(methylthiomethyl)-, 4-(methylsulfinylmethyl)- and 4-(methylsulfonylmethyl) analogues by germfree rats. Mechanisms for the formation of these metabolites from the mercapturate and the S-glucuronide are proposed. These mechanisms involve the biliary excretion of a mercapturic acid conjugate and an S-glucuronide conjugate which are metabolized in the intestine to metabolites that are reabsorbed, metabolized and excreted with the urine.