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Measurement on 3,4-benzopyrene- and methylcholanthrene-induced tumours of the rat (and mouse) showed that the multiple established manipulated hyperacidification of transplantation tumours to values about pH 6 is possible also on autochthonous tumours.
Forty hamsters received weekly installations of benzopyrene into the larynx. Twenty of these also had 10% alcohol as their total liquid intake. Carcinoma of the larynx was seen in seven alcoholic vs two nonalcoholic hamsters, supporting the evidence in humans that alcohol is a factor in epidermoid carcinogenesis of the larynx.
The reduction on peroxidation caused by benzopyrenes by some naturally occurring antineoplastic agents was studied in this experimental work. Inhibition/reduction of experimental carcinogenesis induced by benzo(a)pyrene by vitamin C alone and by vitamin C/vitamin E and selenium/ glutathione was attempted in 224 female Wistar rats divided in four groups. Injected with 10.08 mL benzo(a)pyrene, the animals were treated with some naturally occurring substances like vitamin C alone and a combination of anticarcinogens. By calculating the carcinogenic potency of benzo(a)pyrene and the anticarcinogenic potency of substances used as well as histological examination of developed tumors and survival time of treated animals, it was found that vitamin C exerts a significant anticarcinogenic effect of 8.3 units and that the combination of the two anticarcinogens used produced a significant prolongation of the animals survival time with anticarcinogenic potency of 22.1 and 22.2 units, respectively. This is considered a potent anticarcinogenic effect. The question of an additional supportive administration of such agents complementary to the conventional cancer chemotherapy in humans is raised. Of course, further studies are needed.
Experiments were conducted to determine the effects of polychlorinated biphenyls (PCBs) on vitamin E-selenium nutrition in the chick. Results showed that 10 p.p.m. Aroclor¿ 1254 in the diets of breeding S.C.W.L. hens increased the susceptibility of progency to vitamin E-selenium deficiency when those chicks were reared on a diet deficient in vitamin E and supplemented with a marginal level of selenium. Susceptibility to this deficiency, as measured by the incidence of exudative diathesis, was also increased when PCBs were added to chick diets. Dietary PCBs were shown to induce hepatic microsomal benzopyrene hydroxylase and induction of this activity was associated with decreased biological utilization of dietary selenium. PCBs were shown to increase the apparent requirements of the chick for vitamin E and selenium for prevention of exudative diathesis. However, discrimination between effects on vitamin E function and effects on selenium function was not possible in these experiments.
The effects of thyroid status upon cyt. P 450 concentration and ethoxycoumarin deethylase, benzopyrene hydroxylase and UDP-glucuronosyltransferase activities in the liver microsome fraction were far more important in partially hepatectomized rats than in control animals. The partial hepatectomy simultaneously lowered the MFO enzymes activities in the hepatic microsome fraction and made them more sensitive to thyroid hormones effects.
The influence of immunoregulating humoral thymus factor T-activin (fraction AFT-6) on the activity of xenobiotic metabolism enzymes (EMX) and cellular-dependent cytotoxicity was investigated in germ-free guinea-pigs. Germ-free and conventional animals were injected 5 micrograms of T-activin intraperitoneally, on 3 successive days. The control animals were injected a physiologic saline. A day after the last injection the animals were killed, and EMX and K cell activity was measured. It was found that EMX activity in germ-free animals was decreased. T-activin stimulated cytochrome P-450, NADP-cytochrome-C-reductase, glutathione-S-transferase, benzopyrene hydroxylase and epoxyhydrase activity. In conventional animals the activity of these enzymes remained unchanged under the influence of T-activin. K-cell activity in germ-free animals was decreased, as compared to conventional guinea-pigs. Under the influence of T-activin the parameter increased and stood at about 70% of normal values.
A single oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rats at a dose level of 25 microgram/kg produced marked proliferation of smooth endoplasmic reticulum in renal proximal tubule cells of the straight (S3) segments. This ultrastructural effect was associated with a pronounced induction of the microsomal enzymes glucuronyl transferase and benzopyrene hydroxylase which persisted for at least 16 days after treatment. Renal dissection studies disclosed that the activities of these enzymes in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated animals were not uniformly distributed within the kidney but followed the general known distribution of S3 cells. Enzyme activities were highest in the outer stripe of the medulla and cortex and lowest in the medulla. These studies demonstrate that the kidney does possess inducible microsomal enzyme systems, capabilities of which have not been appreciated previously due to the lack of a suitable inducing agent and their apparent concentration in a relatively small population of proximal tubule cells.
Within the sphere of the researches the biological effects of the most common edible oils (peanuts, sunflower, maize, soya and rectified olive) it has been studied the interaction between the development of the Euglena gracilis unicellular seaweed and the presence of the unsaponifiables examined in their cultures. As a biologically active substance it has been used 3,4-benzopyrene. Spectrophotometric analysis have evidenced that all the unsaponifiables, especially those of the soya seeds, caused a growth decrease of the seaweed culture. A similar effect is found in the cultures treated with aromatic hydrocarbon.
Antitumor activity of bamboo leaf against various transplantable mouse tumor strains, such as Sarcoma 180 and Ehrlich ascites carcinoma has previously been demonstrated by Sakai et al.7) and Yammamoto et al.9). The present investigation was undertaken to determine the antitumor activities of BLE and BLL against the spontaneous tumor induced by benzopyrene (BP) and 4-nitroquinoline-1-oxide (4NQO) in mice and rats. The possible mechanism of antitumor action was also discussed as related to Kada's Rec-assay and Ames test in vitro. The in vivo antitumor test was performed using 16 groups of mice given the following solutions ad libitum for 120 days; Groups 1-4, 5-8, 9-12 and 13-16 were given water, 1% and 10% BLe, 0.1% BLL, and each respective group was treated with no injection (control), oil/s.c., BP 1 mg/s.c., and 4NQO 0.5 mg/s.c. Rat respective group was treated 30 days after in initiation of experiment with no injection (control), oil/s.c., BP 2.4 mg/s.c. Antitumor activities of the BLE and BLL were determined by the tumor incidence index and average weight of tumor. In vitro Rec-assay, cold incubation method, and Ames test were performed in the usual manner. Antitumor activity against BP induced tumor was the highest with 1.0% BLE (0.71 mg/ml), but no significant difference was found between the groups of the 10% BLE, 0.1% BL and control. A weak trend toward DNA damage was seen in the case of BLE, in the Rec-assay. His+ revertants with S-9 mix on Salmonella typhimurium TA98 were found in the case of BLL. It was concluded that antitumor activity against BP- and 4NQO-induced tumors was the highest with 1% BLE (0.71 mg/ml), and a direct action of BLE on tumor cells was indicated.
Styrene is commonly used in western Europe for the manufacture of plastics suitable for packaging foodstuffs. This report demonstrates that, injected intraperitoneally at a dose as low as 10 mg/kg, styrene modifies the catalytic properties of aryl hydrocarbon hydroxylase by reducing its KM value. A similar effect is reported for two potent chemical carcinogens, 3-methylcholanthrene and benzo(a)pyrene. Ethylbenzene and benzo(e)pyrene and phenobarbital do not produce the same effect. Pretreatments of the rats with chemicals which modify aryl hydrocarbon hydroxylase also increase the capacity of the liver enzymes to activate benzopyrene to a mutagenic intermediate in vitro, as measured by the Ames test for mutagenicity. Exposure to both styrene and the other modifiers of the xenobiotic-metabolizing enzymes could thus influence the carcinogenic and toxic effects of chemicals which are activated by these enzymes. This hypothesis needs further investigation.
Cellular uptake of crystalline Ni3S2 particles (a potent carcinogen) and amorphous NiS particles (a noncarcinogen) were studied using light and electron microscopy. Cultured Syrian hamster embryo cells and Chinese hamster ovary cells actively phagocytized Ni3S2 particles (less than or equal to 5 micrometer) but did not take up NiS particles (less than 5 micrometer). For example, within 30 min after addition of Ni3S2 (high dose) to cell cultures, 12.5% of the cells contained nickel particles in the cytoplasm. Within 6 hr, 75% of the cells had engulfed Ni3S2 particles. Cultures exposed to NiS under similar conditions had less than 1.0% of the cells containing particulate nickel within 6 hr. The uptake of Ni3S2 was related to the particle concentration and duration of exposure. Concentration-dependent morphological transformation was induced by Ni3S2 in Syrian hamster embryo cells, but similar treatment of cells with amorphous NiS resulted in no morphological transformation. Pretreatment of Syrian hamster embryo cells with benzopyrene enhanced the cellular uptake of Ni3S2 particles and also the incidence of Ni3S2-induced morphological transformation. Our results suggest that the carcinogenic activity of particulate Ni3S2 is related to its cellular uptake.
The determination of lipids in cultivated animal cells (aortic smooth muscle cells and L cells) by pulse cytophotometry is described. The cells were stained with phosphene 3 R and benzopyrene caffeine. By standardization of the procedure a reproducible quantitative evaluation was possible.
The microsomal fraction of sheep vesicular glands has been found to oxygenate 1,3-diphenylisobenzofuran, luminol, and the carcinogenic hydrocarbon benzopyrene when incubated with arachidonic acid. The oxygenations demonstrate an absolute dependence on enzyme and fatty acid and can be completely inhibited by indomethacin and 2,3-dimercaproptopanol, inhibitors of prostaglandin synthetase. The oxygenations can also be stimulated by the hydroperoxy endoperoxide, prostaglandin G2, and 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid. These latter reactions are not inhibited by indomethacin or dimercaptopropanol but do require the microsomal enzyme system. The involvement of superoxide anion in the transformations could not be demonstrated. The oxygenations occurring in the presence of arachidonic acid appear to arise via the interaction of a microsomal enzyme system with hydroperoxide intermediates of prostaglandin biosynthesis. The ability of various sulfur reagents (reduced glutathione, alpha-lipoic acid, methional) to inhibit co-oxygenation is probably related to their ability to stimulate the conversion of the intermediate to prostaglandins.
The presence of 3,4-benzopyrene is reported in samples of water and sediments from three briny ponds free from pollution of exogenous origin belonging to three different atolls of Polynesia. The synthesis of this hydrocarbon seems to be dependent on the presence of abundant phytoplancton and of bacterial flora.
The discussion about the possible consequences from the agricultural use of composted sewage sludge; which contains considerable amounts of polycyclic, aromatic hydrocarbons (PAH), caused us to investigate the normal concentrations of these substances in soil from agricultural land. In 50 soil samples, mainly from various parts of the Federal Republic of Germany the following 6 PAH were determined: fluoranthene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, benzo(ghi)perylene, indeno(1.2.3-cd)pyrene. In 74% of the samples benzopyrene concentration was between 2 and 50 microgram/kg, and the sum of the 6 compounds between 50 and 500 microgram/kg. No smaller values were found, and higher concentrations in most cases could be connected to some source of pollution.
Derivative non-linear variable-angle synchronous fluorescence spectroscopy (D-NLVASFS) has been developed to improve the selectivity of the fluorescence measurement without loss of sensitivity. We report a simple screening approach for the rapid and simultaneous determination of 1,2.5,6-dibenzoanthracene (DBA), 2,3-benzofluorene (BF), pyrene (Pyr) and 3,4-benzopyrene (BaP) in a mixture by using first-derivative NLVASFS. The method is efficient, fast and straightforward, and the measurement was simply based on a single spectrum via a single spectral scanning of a sample. The linear ranges 0.005-0.30, 0.02-0.30, 0.02-0.40 and 0.005-1.0 microg/mL and the detection limits 0.08, 1.14, 1.64 and 0.12 ng/mL are obtained for DBA, BF, Pyr and BaP, respectively. The method was applied to water samples spiked with the four polycyclic aromatic hydrocarbons (PAHs), with mean recoveries of 103.0% (SD 5.9%) for DBA, 96.4% (SD 4.2%) for BF, 96.2% (SD 4.0%) for Pyr and 98.2% (SD 3.0%) for BaP.
CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.
We studied the mechanisms of platelet activation by sublines exhibiting different metastatic potential of two murine experimental tumors: sublines M4 and M9 of the benzopyrene-induced mFS6 sarcoma and sublines B77-AA6 and B77-3T3 of RSV-transformed BALB/c 3T3 fibroblasts. The neoplastic cells of both models induced platelet aggregation, secretion and prostaglandin biosynthesis. In the first model but not in the second, all these processes correlated with the in vivo malignancy of cells. Pretreatment of B77-AA6 and B77-3T3 cells with apyrase significantly decreased platelet aggregation, while pretreatment of M4 cells was ineffective. However, pretreatment with trypsin or neuraminidase was effective in reducing platelet aggregation induced by M4 cells, but not that induced by any of the others; furthermore, phospholipase A2 reduced the platelet response by all sublines. Finally, platelet-activating activity was also found in the pellets obtained following centrifugation of culture media. These results suggest that platelets are stimulated by cancer cells through different mechanisms; platelet activation by a sialo-lipo-protein complex of the cellular membrane was found to be characteristic of the model in which the platelet-aggregating activity of neoplastic cells correlated with their in vivo metastatic behavior.