Pulmonary cytochrome P-448 from 3-methylcholanthrene-pretreated rats was partially purified approximately 20-fold. The purified preparations containing 1.74 nmol per mg protein were essentially free of NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase, and included a small amount of cytochrome b5 spectrophotometrically. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the partially purified cytochrome P-448 gave one major band and several minor bands when stained with Coomassie blue. The major band on which the presence of peroxidase activity could be determined had the apparent molecular weight of 57, 000. In the presence of NADPH-cytochrome c reductase, lipid and NADPH, the pulmonary cytochrome P-448 was active in hydroxylation of benzo-[a] pyrene, but catalyzed N-demethylation of benzphetamine in a slow rate.
The oral administration of CCl4 (2.5 ml/kg) to male rats induced increase in the activity of serum GPT, accumulation of hepatic triglyceride, accerelation or depression in the activities of microsomal enzymes, disaggregation of hepatic polyribosomes, and decrease in the ability of in vitro protein synthesis 0.5 hr after the intubation. When, however, a small dose of CCl4 (0.25 ml/kg) were given, the defects in hepatic polyribosomes and mixed-function oxygenase system were most marked among the above toxic changes.
The subcutaneous administration of chloropeptide, a hepatotoxic cyclic pentapeptide of Penicillium islandicum Sopp, induced a marked enlargement of hepatic weight in mice. Chemical analysis revealed an increment of water content. Biochemical investigation resulted in marked elevation of serum enzyme activities such as transaminases, alcohol dehydrogenase, fructose-1-phosphate aldolase and lactate dehydrogenase.
Age difference of cadmium retention was investigated in hamsters after a short term cadmium exposure. Three types of organs were identified in relation to cadmium retention, i.e., the liver and testes retained an increasing amount of cadmium with increasing age, the kidney and heart showed a gradual decrease in the retention after a transient increase in young ages and the bone showed no retention. These changes seemed to be related to the de novo synthesis of metallothionein in the organ.
Microbial backward mutation. test, Ames Salmonella / microsome plate assay, on six bacterial strains (Salmonella typhimurium TA 98, 100, 1535, 1537, 1538 and E. coli WP 2uvrA) and micronucleus test in mice were carried out to detect mutagenic activity of mequitazine. Mequitazine caused no increases of revertants at doses from 1 to 1000μg/plate in every bacterial strains irrespective of metabolic activation. Similarly, mequitazine induced no Significant increases of micronucleated polychromatic erythrocytes in mice over the control level at doses from 0.12 (clinical dose) to 48mg/kg (approx. LD 50). From above results, we concluded that mequitazine has no mutagenic activity per se.
Subacute toxicity and recovery tests of Mequitazine, a new phenothiazine type anti-histamine agent, were carried out using each 20 male and female dogs. The drugs was administered orally in doses of 0, 1, 5 and 25 mg/kg day for 14 weeks. Recovery test was carried out for following 4 weeks. As a result, transient decrease of the body weights and somnolences were observed in both male and female dogs given 25 mg/kg. In a female dog given 25 mg/kg, extrapyramidal reaction accompained with tremors and muscle stiffenings was observed. But no dead animals were observed throughout experimental period. Vomitings, mydriasis and loss of appetite were observed with the dose-responsiveness, but these symptoms were reduced after 1-2 weeks administration. No abnormal changes were observed in hematological, serum biochemical, and other examinations. In histopathological examinations, slights changes were observed in liver, kidneys, mesenteric lymph nodes, palpebra and conjunctival membrane. But these changes were reversible in recovery period. From these results, it was suggested that the maximum non-effective and maximum safety dises were 1 mg/kg/day and 5 mg/kg/day, respectively.