P. Benard

Gamma Glutamyl Transferase in domestic animals

In domestic animals, Gamma Glutamyl Transferase is mainly in the kidneys, the pancreas and the intestine; its liver activity is relatively high in cows, horses, sheep, and goats and very low in dogs, cats and birds. The use of plasma reference values can help to interpret the variations of serum GGT mainly in hepatobiliary diseases of cattle, sheep, goats and cholestatic disorders of dogs. Urinary GGT is a good test of kidney toxic damage.

La gamma-glutamyl transferase urinaire en toxicologie renale chez le rat. Bases de son utilisation-interet lors de nephrite aigue mercurielle

Summary Kidney specificity and toxicological value of urine gamma-glutamyl transferase (GGT) have been investigated in the rat. At first, it was checked in 30 Cobs rats that urinary GGT originates only from kidney and not from other parts of the genito-urinary tract. Conditions of urine collection and of activity measurement were studied: (1) urine GGT was stable at room temperature and at +4°C, but was rapidly inactivated by freezing, (2) GGT activity in urine was measured without prior dialysis after a 5 mn centrifugation at 3000 g and a dilution in saline (1/10, v/v). Reference values in Cobs rats weighing 250–350 g were: 381 ± 139 U/1 or 3.73 ± 1.43 U/24 h for males and 205 ± 79 U/1 or 1.89 ± 0.57 U/24 h for females (P In acute mercuric nephropathy resulting from single injection of 0, 0.25, 0.50, 1.0, 1.5 mg Hg/kg (HgCl2, i.p.), GGT activity in urine was compared with the following parameters: volume, sodium, potassium, chloride, urea, creatinine and alkaline phosphatase (PAL). Urine GGT was rapidly and intensively increased, more than PAL and volume, whereas the other parameters are lowered. More sensitive than kidney function tests, as sensitive as histology but performable in vivo, as specific as other urine enzymes but easier to measure without prior dialysis of urines, urine gamma-glutamyl transferase is a very good test for kidney tubular lesion.

Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract ofSerenoa repens (Permixon®) supplemented with [1-14C]-lauric acid, [1-14C]-oleic acid or [4-14C]-β-sitosterol

SummaryThe study carried out on rats given orally then-hexane lipido/sterolic extract ofSerenoa repens (LSESR), supplemented with [14C]-labelled oleic or lauric acids or β-sitosterol, demonstrated that radioactivity uptake in prostatic tissues shows the highest level in th case of administration of LSESR supplemented with [14C]-labelled oleic acid. This was clearly demonstrated on a rat with an induced fibro-muscular hyperplasia of the prostate and by quantitative measurements of radioactivity. Ratios of radioactivity in tissues compared to plasma show an uptake of radioactivity greater in prostate as compared to other genital organs, i.e. the seminal vesicles or to other organs such as liver.

Urine gamma-glutamyl transferase in rat kidney toxicology: nephropathy by repeated injections of mercuric chloride. Effects of sodium selenite.

Groups of 5 male and 4 female Cobs CD rats weighing 250--350 g were injected intraperitoneally, daily for 15 days, with 5 mumol HgCl2/kg, 5 mumol Na2SeO3/kg, or (5 mumol HgCl2 + 5 mumol Na2SeO3)/kg in a 10 ml/kg vol. of saline. Control animals were injected with saline only. Injection of saline or sodium selenite produced neither modification of diuresis, nor of urine elimination of sodium, potassium, chloride, phosphates, urea, creatinine and gamma-glutamyl transferase (GGT). Injection of mercuric chloride induced a massive increase of urine GGT, diuresis and phosphaturia and a decrease of kaliuria and natriuria. Those effects reflect a kidney tubular lesion which seems to be more severe in males than in females. Injection of mixed sodium selenite and mercuric chloride or separate injection of both compounds had similar effects. In both sexes, urine GGT elimination was delayed and about 2 times lower than with HgCl2 alone. In females, the other urine parameters were almost normal whereas in males, diuresis and phosphaturia were slightly increased and kaliuria decreased. The observation of urine GGT elimination attests, in vivo, that sodium selenite decreases tubular toxicity of mercuric chloride and resulting kidney function disturbances.

Acute kidney toxicity of sodium fluoride in the rat.

Single i.p injection of 0, 0.05, 0.10, 0.25, 0.50 and 1.00 mmol NaF/kg to male rats induced a dose-related increase of urine gamma-glutamyl transferase (GGT) elimination on the first day for all doses higher or equal to 0.25 mmol NaF/kg. Kidney damage began between 2--4 h following the injection and lasted only 12 h for the 0.50 mmol NaF/kg dose. There was an increase of diuresis and of phosphaturia even at lower doses.

Application of whole-body autoradiography in toxicology

Whole-body autoradiography enables the drugs and toxicants to be distributed throughout the animal. Good results are obtained with this technique. However, certain artifacts can occur that could lead to misinterpretation, and these must be known. These artifacts are described. From the metabolic point of view, autoradiography provides data on the distribution kinetics of a compound and the elimination of radioactivity in various organs. These data are a guide for quantitative research into the metabolism of a compound. From the toxicological point of view, it must be admitted that the main purpose of this technique is to reveal the sites of retention of radioactivity. Such specific organ retention could be the consequence of the activation of a minor metabolite into a very reactive compound. If this is so, it is a specific organ effect which could not be studied by other techniques and could lead the way to a more specific organ effect which could not be studied by other techniques and could lead the way to a more appropriate line of research in the study of chronic toxicity. However, it must be recalled that the fact that a compound is retained by a specific organ does not always mean that the compound exerts a toxic effect upon the said organ. With this technique, distribution study can be performed on pregnant animals, and it provides us with more data concerning the transplacental passage of radioactive metabolites. All these aspects of the technique clearly indicate that whole-body autoradiography should be insisted upon during the early stages of development of new molecules. Successive experiments could then lead to selecting the best experimental conditions for metabolic pharmacokinetics and studies in toxicology.

Methoxyethylmercury nephrotoxicity: effects on enzymuria and kidney function

The fungicide, methoxyethylmercury chloride, was given in a saline solution to four groups of Sprague-Dawley C D rats (5 ♂, 5 ♀) as a single injection (IP) of 0, 0.5, 1.0, and 2.0 mg Hg/kg. In a three-day period, no changes were observed in urine collected every 24 h from rats given 0 or 0.5 mg Hg/kg; 1 mg Hg/kg induced only a transient increase of urine gamma glutamyl transferase (x 4) and alkaline phosphatase (x 2.5) on the day 2; 2.0 mg Hg/kg caused an early increase of enzymuria (day 1 and day 2) and a decrease of Na+, Cl−, K+, urea, and creatinin excretion. Urine enzymes and total mercury excretion were higher in males. These time-related variations of enzymuria, compared to previous results with Hg Cl2, could reflect the existence of metabolites more toxic than the native compound.

Distribution and tumor penetration properties of a radiosensitizer 2-[14C] misonidazole (Ro 07-0582), in mice and rats as studied by whole-body autoradiography

SummaryThe hypoxic cell radiosensitizer 2-[14C] misonidazole: 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol (Ro 07-0582) MISO was administered to mice, control rats, and rats bearing chemically induced rhadbdomyosarcoma. The dose injected was 250 mg/kg and the delivered activity was 100 μCi/kg. Whole-body autoradiography was performed in all animals. We noted the highest uptake of radioactivity in the liver and the kidney. In the liver there was an accumulation of [14C] from 5 min to the 2 hour after treatment, followed by a decrease; this observation is probably related to the metabolic pathway of the drug. The radioactivity was also concentrated in the renal medulla (30 min after injection); this organ is the excretion route for most of the misonidazole or its metabolites. Fecal excretion is also important following biliary elimination. Radioactivity is present in the central nervous system in the first hours after dosage. [14C] Tumor activity was lowest 5 min after IP treatment. By contrast, 12 h after administration of labeled compound the highest activity was detected in this tissue.

Autoradiographic study of14C-Sulpiride in monkey

SummarySubstituted benzamides have been the object of numerous metabolic studies including many by whole body autoradiography of rats and mice.The present study reports autoradiographic data concerning14C-labelled Sulpuride in monkey. The Study was limited to the brain in order to elucidate the controversial question as to whether the drug can cross the blood-brain barrier. The results showed that in monkey, as in rat and mouse, there is no localization in the brain as can be clearly seen on the autoradiograms. In view of these results and of the undeniable neuroleptic properties of Sulpiride, an indirect mode of action through the release of endogenous mediators is proposed.

Acute kidney disturbances by lead acetate in the rat.

Four groups of 5 male and 5 female rats were dosed i.p. with 0, 0.05, 0.15 and 0.30 mmol Pb2+/kg as neutral acetate. A minimal kidney damage shown by an increased urinary GGt was only observed in males at the highest dose. In all animals and for all doses natriuria was significantly decreased on the first day (from the 4th hour). Such disturbances evoke mild tubular disturbances but glomerular disturbances may also be involved.