Biomedical subjects
Publications and source records attributed to R Truhaut.
During detoxication processes of DDT, there is, in the Rat, interference between vitamins A and E (D.1.alpha-tocopherol acetate). Vitamin E spares retinal and has a slighter but significant influence on P 450 cytochrome induction. These results are discussed.
Consumption of vitamin A and cytochrome P 450 by pregnant Rat is more important than in non pregnant and ovariectomised Rat. Estradiol implant in ovariectomised female has some, but slighter, influence only on retinol. These physiological situations have no action on the hepatic levels of tocopherols (total and alpha). These results are discussed.
There are significant differences between castrated and non castrated male Rats in regard to vitamine A hepatic storage and plasma level. Cytochrom P 450 levels are the same in both groups. Those results are discussed.
The possible influence of a potent enzyme inducer, phenobarbitone, on white phosphorus fatty liver, was studied. Pretreatment by phenobarbitone for four days in white phosphorus poisoned rats provoked a decrease in mortality and an increase in hepatic triglycerides (fatty liver) in male rats. The activity of uridine diphosphoglucuronyl transferase (UDPGT), an inducible enzyme, is not modified by this pretreatment in white phosphorus poisoned rats. The accentuation of white phosphorus fatty liver by phenobarbitone in male rats could be explained by an increased hydroxylation of testosterone, thus counteracting the protective effect of this hormone on fatty liver.
The steatogenic effect on the liver of Rifampicin, a potent inhibitor of the DNA-dependent RNA polymerase in bacteria, was investigated in male and female rats which received either 200 mg or 400 mg of Rifampicin/kg/24 h for 8 days. The determination of total lipids (TL), triglycerides (TG), total cholesterol (TC) and phospholipids (PL) showed a significant increase of TL, TG and TC in the liver at a dose of 400 mg. There was better reproducibility in the male whose blood TG and PL were significantly decreased. These results showed that fatty liver can be induced by very high doses of Rifampicin in rats. A blockage of the very low density lipoproteins (VLDL) biosynthesis and/or secretion can be expected. As a potent steatogenic toxin, alpha-amanitin, is a strong inhibitor of RNA polymerase II in eukariotic cells, a relationship between the RNA polymerase inhibition induced by both of substances and a subsequent inhibition of the biosynthesis of the protein moiety of lipoproteins can be considered. Nevertheless Rifampicin is at present not considered as an inhibitor in eukariotic cells and it will be of great interest to test such a possibility with the high doses used in these experiments, in further work.
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Toxicological evaluation in quantitative terms of substances that have been shown to be carcinogenic is very difficult, mainly because, for the great majority of environmental carcinogenic chemicals, the available data, both from experimental studies in animals and from epidemiological studies in humans, on dose-effect relationships, especially at low levels, are very limited. There is an urgent need for research in this area. At present, the most sensible approach is to try to determine no-effect levels by long-term investigation of the effects of low levels in animal species that are most similar to man in their metabolic potential and their sensitivity. Very low safety factors (2500 to 5000) should be applied to the values thus obtained, in order to be as far as possible on the safe side in establishing pragmatically acceptable limits. At present, since all chemical carcinogens pose a hazard, human exposure to them must be reduced to the feasible minimum.
Besides novel routes of biotransformation of xenobiotic substances recently reported, such as N-glucuronidation of teritary amines and quaternary ammonium componds, N-glucosylation, N-carbamylglucuronide formation from a primary amine, C-glucuronidation, conjugation with long-chain fatty acids, with polypeptides, carbon-chain elongation, stereospecific inversion of configuration at a satured carbon atom, formation of methylthio metabolites, the authors have described a new metabolic pathway: dismutation, in the case of 3,5,5, - trimethylcyclohexanone (dihydroisophorone). As a matter of fact, this compound leads, in vivo, to the formation of isophorone alpha and of cis and trans 3,5,5, - trimethyl cyclohexanols. These compounds, extracted from the urine of treated rats and rabbits, have been identified by gas-liquid chromatography and thin-layer chromatography.
Inhalation of an oily aerosol of bis (tributyltin oxide) (TBTO) after single or repeated expositions (1 hour) disturb the exploratory behaviour in the mouse. Weak concentrations (42 and 84 ppm) stimulate exploratory activity while large doses (170 and 340 ppm) significantly decrease it. Modification in brain amine levels may appear but the observed perturbance seems to be more dependent from oily vehicule than TBTO itself.
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Two platinum derivatives, cis-PtCl2(NH3)2 and PtCl6(NH4)2 have been studied for their effects on the Rat on cytochrome P450 in hepatic parenchyma on zoxazolamine-hydroxylase, a typical inducible system and on the two isoenzymes of dimethyl-nitrosamine demethylase, typical repressible systems. The inhibitory effect of PtCl6(NH4)2 on zoxazolamine-hydroxylase activity, previously shown by the authors, has been confirmed. The cis-PtCl2(NH3)2 also significantly inhibits zoxazolamine-hydroxylase activity. On the other hand, both of the platinum derivatives decrease cytochrome P450 level and enhance the dimethyl-nitrosamine metabolism. These various effects and their relationship are discussed.
The possible induction of fatty liver by Rifampicin has been investigated by oral administration of two different doses (200 and 400 mg/kg/24 h) of this antibiotic for a period of 8 days to male and female Rats. The results obtained are more constant and more coherent in male than in female. It is the 400 mg/kg/24 h dose which is more effective, leading to an increase of lipids, triglycerides and cholesterol in the liver and a decrease of serum triglycerides. A dose-effect relationship may exist. These preliminary data lead us to believe that Rifampicin may inhibit the synthesis of the protein moiety of lipoproteins, such as alpha-Amanitin, which is also a RNA-polymerase inhibitor.
Phenobarbital administration to the Cat an animal hypersensitive to the actions of many toxic substances or to physiological compounds such as hormones, does not produce cytochrome P 450 induction. Consequently, hepatic storage of retinol remains unchanged. The specific and original characteristics of the Cat in this field are underlined by these results.
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To check the possible toxicity risks of the meat from swine fed with a residue producing feed additive: Carbadox, a new methodology was used. It is the "Relay Toxicity". Swine were fed with a high dose of the additive and sacrificed without any withdrawal. In such conditions meat contains a high level of residues. The frozen meat was given daily--after thawing--at 100 g or 200 g/dog to 12 beagle dogs, 6 females and 6 males, sacrificed when 87.5 months old (85 months on experiment). On these animals, no anomaly was found: on weight gain and health; on fertility and reproductive performances; on hematology and biochemical values of blood and urine; and after careful macroscopic or microscopic examinations of the animals at safrice. We were able to obtain a safety factor above 9000 when Carbadox is used at the maximum level approved 50 ppm, and the withdrawal 4 weeks before slaughtering. To conclude, the absence of anomaly allows us to confirm the safety for the human consumer when Carbadox is used as a feed additive for swine.
Aramite has been administered to male rats by oral route during 56 weeks at a daily dose of 400 mg/kg. There was a decrease of the body weight and several animals died. Liver hypertrophy was observed with neoplasic proliferation of parenchymatous cells and cholangiocarcinoma.