To comparably investigate hemotoxic potentials of CdCl2, cadmium-saturated metallothioneins-I (Cd-MT-I) and -II (Cd-MT-II), rats received single intravenous injections of one of those dissolved in saline with equivalent concentrations of Cd (0, 0.1, 0.3 and 1.0 mg Cd/kg body weight), and blood for hematological examinations was sampled at 1 and 5 days (Days 1 and 5) after the administrations. The counts of white blood cells showed dose-dependent increments in the 0.3 and l.0 mg Cd/kg groups in Cd-MT-I and Cd-MT-II at Day 1, and returned to the normal levels at Day 5. The counts of platelets showed dose-dependent decrements in the three-doses groups of Cd-MT-I and Cd-MT-II at Day 1, and did a returning- and further increasing tendency at Day 5. The counts of red blood cells, values of hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, showed only slight and sporadic changes at Days 1 and 5. As to that thrombocytopenia and leukocytosis were dose-dependently brought by Cd-MTs and not by CdCl2, and as to that CdCl2 and Cd-MTs hardly affected erythrocytes regarding their counts, sizes, hemoglobin contents etc., etiological mechanism (s) remains to be explored. However, our findings should be clinically emphasized in relation to Itai-Itai disease and Cd-intoxication.
Some of antihypertensives, opiate antagonist and antifungal agent can interfere with sexual function in both men and women. Drug-related effects on sexual function may be difficult to distinguish from the direct action of gonadal function. Clinically well known those agents to have sexual dysfunction were selected and examined the direct effect on rat's testicular steroidogenesis in vitro. Donryu rats were decapitated at 11 weeks old and isolated testes were decapsulated and preincubated with Krebs-Ringer-phosphate buffer (KRP) added with 1μg/flask of LH for 60 min at 37°C. Then, incubation was made with prazosin (1μg), clonidine (5μg), verapamil (10μg), naloxone (5μg) and ketoconazole (150μg), 37°C for 180 min in fresh KRP-buffer, respectively. Steroids were analysed with RIA, and microfluorometry after purification with quantitative thin layer chromatography. Prazosin had a tendency to produce dihydrotestosterone (DHT) indicating a facilitation of 5α-reductase, and clonidine showed a significant production of estradiol (E2) with a slight production of DHT indicating a significant facilitation of aromatase. Verapamil had a action to produce significantly E2 with a slight production of DHT, and naloxone showed a significant production of both DHT and E2. Thus, these two agents showed facilitation of both 5α-reductase and aromatase. Ketoconazole had a significant production of both Δ4-androstenedione (Δ4-A) and E2 while it had a significant inhibition of DHT-production, thus this had a significant production of both aromatase and C<17, 20>-lyase while had a significant inhibitory action of 5α-reductase. These findings indicates that comparatively large doses of central-nervous system depressants are one of the factors that interfere with sexual function, but it is not necessary to have direct action to testicular function, however present study revealed that some of them can cause gonadal damage and consecuently progressive loss of libido.
A chronic feeding study was carried out in Wistar rats using microencapsulated bromodichloromethane. The test substance was administered in the diet at doses of 0, 0.014, 0.055 and 0.22% for 24 months. Rats were sacrificed after 6, 12, 18 and 24 months of continuous dosing. The results showed a suppression of body weight gain in the 0.22% group for both males and females. Dose related changes were clearly observed in the liver with histopathological findings including fatty degeneration in the 0.014% or higher dose male groups, and fatty degeneration and granuloma in the 0.055 and 0.22% group females, as well as bile duct proliferation and cholangiofibrosis in the 0.22% group for both males and females. No significant differences in incidences or numbers of neoplastic changes were seen between control and any of the treatment groups. There were no dose-related non-neoplastic lesions in the kidneys of either sex. Lowest-observed-adverse-effect-level was determined to be 6.1 mg/kg/day under the present experimental conditions.
The effects of acute administration of chlorpromazine (CPZ) and perphenazine (PPZ) on hepatic microsomal phospholipids (PLs) and enzyme activities in the male rat were examined in order to elucidate the relationship between individual PLs and drug-metabolizing activity. Cytochrome P-450 and aniline (AN) hydroxylation activity were initially decreased in CPZ-treated rats, but cytochrome P-450 subsequently recovered to a level not significantly different from the control and AN hydroxylation was markedly increased, while in PPZ-treated rats, they remained depressed. CPZ increased the activities of glycerophosphate acyltransferase (GPA) and choline phosphotransferase (CPT), while PPZ increased the activities of phosphatidate cytidylyltransferase (PCT), phosphatidate phosphohydrolase (PPH) and CPT. Concurrently, CPZ raised microsomal phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine-inositol (PSI) and sphingomyelin (SM), while PPZ increased PC and PE, but did not affect the levels of PSI and SM. Acyl components of phospholipids were also modified. CPZ significantly decreased the ratio of saturated to unsaturated fatty acids, particularly in the PC and PE fractions, while the effect of PPZ was only slight. The results imply that an increase of AN hydroxylation activity may involve the incorporation of unsaturated fatty acids into enzyme-associated PC and PE.
The behavioral effects of methylxanthines, caffeine, theophylline and theobromine, were compared by means of ambulatory activity and discrete lever-press avoidance response in mice. The single oral administration of 10-100 mg/kg of caffeine, 30-300 mg/kg of theophylline, and 10 mg/kg of theobromine singnificantly increased the mouse's ambulatory activity. However, 1000 mg/kg of theobromine decreased the activity. The ambulation-increasing effect of methamphetamine (2 mg/kg s.c.) was enhanced by coadministration with caffeine (3-100 mg/kg), theophylline (10-300 mg/kg), and theobromine (10-100 mg/kg). On the other hand, comparatively higher doses of caffeine (up to 30 mg/kg) slightly but significantly decreased the avoidance rate without eliciting any significant change in the response rate. Theobromine significantly decreased the response rate at higher than 300 mg/kg, and the avoidance rate at higher than 100 mg/kg. Furthermore, 1000 mg/kg of theobromine was much toxic for mice, i.e., half mice died within a few hr after the end of the 1-hr avoidance session. Theophylline did not produce any significant change in the avoidance response at the dose range of 3-300 mg/kg. These results may indicate the relative order of the centrally stimulant and/or behavioral toxic actions of methylxanthines in human.