The mammalian kidney is a dynamic and complex organ. Excretion of wastes is a primary function, but the kidney also plays a significant role in the regulation of total body homeostasis. Regulation of extracellular volume and control of electrolyte and acid-base balance are important renal functions. The kidney is a major site for formation of hormones that influence systemic metabolic functions, including erythropoietin, 1, 25 dihydroxy-vitamin D3, and renin. Recent evidence indicates that the kidney produces several vasoactive prostaglandins and kinins. A toxicological insult to the kidney could affect any or all of these functions. Few data are available that define specific cellular or subcellular sites of action of nephrotoxicants. Only rarely have receptors for individual agents been identified. Rather, in many cases it appears that several tissue constituents are influenced by a poison. There are two interrelated reasons for this apparent lack of specificity : (1) in contrast to a pharmacological effect which requires interaction with a distinct endogenous receptor, cell damage due to some chemicals may follow interruption of one or several required cellular functions ; (2) certain kidney cells may be more susceptible to damage merely because they are exposed to greater concentrations of chemicals than are other cells of the body as the result of this organ's unique anatomical and functional features.
When mice were fed on a diet containing 15 % sorbic acid for a period up to 6 months, ether extracts of the intestinal contents of the mice were not mutagenic with Salmonella typhimurium TA 98, but the acidic components, obtained by fractionating the ether extracts, showed slightly mutagenic activity with S. typhimurium TA 98, and they required the addition of liver 9, 000 xg supernatant fraction for mutagenic activation. These results suggested that mutagens were gradually produced in the intestine and moved into the liver where they were metabolically activated. It is possible to presume that liver carcinoma might be attributable to the production of these mutagens.
Effect alterations of methamphetamine by pretreatment of amino acids or their salts on ambulatory activity in mice were investigated to confirm a fact that certain amino acids, particularly monosodium L-glutamate, are added to methamphetamine by the street users, and that the amino acids augment the effect of methamphetamine. The ambulatory activity of mouse was measured by a tilting-type round activity cage of 25 cm in diameter. The amino acids or their salts tested were monosodium L-glutamate, monosodium L-aspartate, gamma-aminobutyric acid L-alanine, L-lysine hydrochloride and L-arginine hydrochloride. A single administration of each chemical at doses of 1 and 2 g/kg i.p. did not induce a marked change in the ambulatory activity in mice. Methamphetamine 2 mg/kg s.c. induced an increase in the ambulatory activity with a peak at 40 min after the administration, and the increased ambulatory activity persisted for 3 hr. The ambulation-increasing effect of methamphetamine was augmented by the pretreatment of monosodium L-glutamate and monosodium L-aspartate at 30 min before the methamphetamine administration, while attenuated by the pretreatment of L-lysine hydrochloride and L-arginine hydrochloride in a dose-dependent manner. Gamma-aminobutyric acid and L-alanine did not affect the effect of methamphetamine. Similar augmentation and attenuation in the ambulation-increasing effect of methanphetanline were induced by the pretreatment of sodium bicarbonate 0.9g/kg i. p. (urinary alkalizer) and ammonium chloride 0.07 g/kg i.p. (urinary acidifier), respectively. The urinary pH level was elevated by the administration of monosodium L-glutamate, monosodium L-aspartate and sodium bicarbonate, and decreased by L-lysine hydrochloride, L-arginine hydrochloride and ammonium chloride. Gamma aminobutyric acid and L-alanine did not elicit a marked change in the urinary pH level. The present experiment confirms the fact in human that monosodium L-glutamate augments the effect of methamphetamine. Moreover, the present results suggest that monosodium salts of acidic amino acids augment, and conversely monohydrochloric salts of basic amino acids attenuate the effect of methamphetamine. The alterations of the ambulation increasing effect of methamphetamine may be due to the urinary excretion rates of the drug through changes in the urinary pH level after the administration of amino acids or their salts.
In order to investigate the effect of cadmium on the regulatory system of the acid-base balance in the kidney, the urinary pH and urinary excretion of acids and alkali were examined in rats. Thirty male Wistar rats were divided into 6 injection dose groups of 0, 0.1, 0.3, 0.6, 1.0 and 1.5 mg of Cd (as CdCl2) per kg of body weight. Subcutaneous injections were given 6 days a week for 4 weeks. The 24-hr urine specimens were collected using a metabolic cage. After 4 weeks urinary pH significantly increased in the 0.6 and 1.0 mg dose groups, but apparently showed a near control value in the 1.5mg dose group. In the 1.0 mg dose group, a rise in urinary pH began at 3 weeks. These results suggest that continuous administration of cadmium causes dysfunction in renal acidification. Since the renal ability to excrete hydrogen ions into urine can be evaluated by measurment of urinary excretion of bicarbonate, titratable acid and ammonium ions, quantitative analysis was done by the alkali titration method. At 4 weeks the amount of titratable acid excretion was significantly decreased in the 0.6 mg dose group and showed the same level as the control in the 1.5 mg dose group. Bicarbonate excretion in the urine was detected in the 0.6 and 1.0 mg dose groups, and the amount of excretion was small in the 1.5 mg dose group. The amount of ammonium ion excretion increased with the increase of the dosage of cadmium. Thus, a change in urinary pH corresponded to the change in excretion of acids and alkali. The near controllevel of urinary pH, and acids and alkali excretion in the higher dose groups suggests that exposure to cadmium does not cause any changes in the ability of the kidney to secrete hydrogen ions in the distal tubule ; however a higher level of bicarbonate in the urine excretion suggests that there was severe damage to the proximal tubule. Moreover, the changes in the renal ability to regulate the acid-base balance was consistent with the change of the renal function of reabsorption of glucose, amino acids and protein.
Morphological changes of the thyroid gland on light and electron microscopy as well as concomitant variation in plasma T3 and T4 levels after oral treatment with sulfonamide at a dose of 2 g/kg for 30 consecutive days were examined in male Wistar rats. Several rats were treated with the same dose by the same route for 15 days and then put to the restoration experiment for 15 days. Plasma T3 and T4 levels significantly decreased as compared with the control in the period from the 1st day to the 30th day of the administration. A significant increase in thyroid weight was seen from the 5th day. On the 30th day, the weight was at last about eight times as heavy as that of the control. Histologically, hyperplasia of the follicles which were lined with high columnar cells was observed. The epithelial cells showed considerable pleomorphism and colloid was virtually absent at this time. As early as on the 3rd or 5th day, the follicular cells were high-columnar in shape on electron microscopy and there was an increase in rough-surface endoplasmic reticulum, the cisternae of which were dilated. Swelling of mitochondria and the absence of colloid were also noted. There were no secretory granules in the cytoplasm and numerous long microvilli projected into the lumens. On the 30th day, the follicular cells became remarkably high-columnar and had small and ovoid nuclei at their base. In the restoration study, numerous dense secretory granules and colloid droplet profiles appeared in the cytoplasm.
Light and electron microscopic observations were made on the anterior pituitary gland of male Wistar rats treated with daily oral administrations of sulfonamide at a dose of 2 g/kg for 30 consecutive days. Several rats were treated with the same dose by the same route for 15 days and then put to the restoration experiment for the equal number of days. Histologically, increase and swelling of thyrotrophs, the cytoplasmic granules of which were stainable with PAS and AF, were found after the 7th or 10th day of treatment. On the 30th day, very large vacuoles were seen in the cytoplasm of these swollen thyrotrophs. On the ultrastructural observation of the cytoplasm of these cells, rough-surface endoplasmic reticulum were well developed with dilated cisternae which varied a great deal in size, and well-developed Golgi apparatus were seen. Many electron-dense round bodies were found in the variously dilated cisternae of rough-surface endoplasmic reticulum. These structures were recognized in some parts of the cisternae of rough-surface endoplasmic reticulum as early as on the 7th or 10th day of sulfonamide treatment. On the 30th day, there were autophagosomes and myelin figures in the cytoplasm of several swollen thyrotrophs. From these retsults, it is concluded that so-called "thyroidectomy cel1s" were found after the 5th or 7th day of the high-dose administration of sulfonamide and more and more increased in number with the repeat of administration. These changes tended to revert in the restoration period.
Carcinogenicity study on cholestyramine, an anti-hypercholesterolemic agent, was carried out using Fischer rats by feeding with a normal pellet diet (control) and with three sorts of the pellet diets in which cholestyramine was admixed in the common diet at the rates of 1.25, 2.5 and 5%, respectively. The animals were fed with these diets for 26 months and a normal diet for subsequent 2 months. Some of the male rats fed with the 5% admixed diet revealed a slight growth retardation and occasionally hemorrhagic tendency, without resulting in severe macroscopic and microscopic lesions of the internal organs and in shortening of the mean survival time as compared with that of the control group. The rates of tumor-bearing animals were high in all experimental groups including the control, but the rates were not considered to be drug-related. Incidences of individual tumors were not significantly different each other between cholestyramine-fed groups and control group. Thus, it was not recognized that cholestyramine induced any drug-related specific tumors and an accelerated growth of any tumors.