[Absorption, distribution, metabolism and excretion of N-cyclohexyl-2-benzothiazyl sulfenamide (CBS), a vulcanizing accelerator, in rats].

Absorption, distribution, metabolism and excretion were studied in rats following a single oral administration of N-cyclohexyl-2-benzothiazyl sulfenamide (CBS) at a dose of 250 mg/kg. About 65% and 24% of the dose were excreted into urine and feces, respectively, for 3 days after administration of labeled CBS (cyclohexyl-14C). Biliary excretion amounted to about 5% of the dose for 3 days. While about 92% of the dose was recovered in urine and feces at a ratio of 1:1 within 3 days when 14C-2CBS was given. No specific organ-affinity was observed in distribution study. Cyclohexylamine and 2-mercaptobenzothiazole were identified as urinary metabolites.

Tris (2,3-dibromopropyl) phosphate nephrotoxicity in the rat: histological and biochemical changes in renal components by 13C-NMR spectra.

Rats receiving a single oral dose of 286.8 mumol/kg tris(2,3-dibromopropyl)phosphate (Tris-BP) showed pyknosis of the renal tubular epithelial cells on Day 1, necrosis on Day 2, regeneration from Day 3 and large nuclei formation from Day 4. 13C-NMR spectra were applied to clarify changes of the renal low-molecular-weight components in the kidney injured by Tris-BP, and sialic acid and inositol were found as the desired marker components. The lesions produced by Tris-BP were characterized by changes in the renal components and enzyme activities. Increases in sialic acid content of the kidney were observed both on Day 1, suggesting destruction of the epithelial cell membrane, and on Day 5, suggesting regeneration accompanied by an increase of inositol content on Days 7 and 10. Renal activity of cytoplasmic enzyme, alanine aminopeptidase, was decreased on Days 1 and 5 and elevated on Days 7 and 10. Lactate dehydrogenase activity showed a tendency to decrease in the kidneys on Day 1 and to increase significantly on Days 2, 5, 6 and 7.

Oxidative deamination of alicyclic primary amines by liver microsomes from rats and rabbits.

1. Substrate selectivity and species difference in the oxidative deamination of the alicyclic primary amines, cyclopentylamine, cyclohexylamine, cycloheptylamine, 1- and 2-aminoindane, and 1- and 2-aminotetralin were studied using liver microsomes from rats and rabbits. 2. The deamination rates of the amines were much greater with liver microsomes from rabbits than from rats. Substrate selectivity resulted in much faster deamination of 1-aminoindane and 1-aminotetralin than of the corresponding 2-amino compounds, especially in rats. 3. When 1-aminoindane and 1-aminotetralin were incubated with rat liver microsomes and NADPH under 18O2, oxygen-18 was incorporated into the deaminated products, 1-indanone and 1-tetralone. The carbinolamine is a key intermediate in the oxidative deamination by rat liver microsomes, indicating the contribution of cytochrome P-450-dependent alpha-C-oxidation to the reaction. 4. Alicyclic primary amines gave type II binding spectra with rat and rabbit liver microsomes, but the spectra appeared to contain type I components. 5. The ratios of the alcohols, cyclohexanol, 2-tetralol and 2-indanol in the deaminated products were high in both rats and rabbits. The ketones were precursors of the alcohols, and substrate selectivity in reduction of the alicyclic ketones with NADPH was similar in both species.

Alkylation of DNA in F344 rat thymus following administration of 1-n-propyl-1-nitrosourea in vivo and comparison of O6-alkylguanine DNA alkyltransferase activity in thymus from F344 and Long-Evans rats in vitro.

The tissue distribution of radioactivity 1 h after i.p. injection of [n-propyl-2,3-3H]1-n-propyl-1-nitrosourea (PNU) (100 mg/kg) was studied in male F344 rats. This treatment results in a high incidence of thymic lymphomas. The 3H concentration in the thymus, testis and brain was significantly higher than that in blood. 7-n-propylguanine and O6-n-propylguanine were detected in thymus DNA of F344 rats treated with PNU; the ratio of O6-n-propylguanine/7-n-propylguanine was 0.35, lower than following DNA alkylation in vitro. This suggests the presence of O6-alkylguanine DNA alkyltransferase (AGT) in thymus. AGT activity in F344 and Long-Evans rats was compared by using a 3H-propylated DNA as a substrate. AGT activity in the thymus of F344 rats was lower than that in the liver. The AGT activity in the thymus of Long-Evans strain, which had a low incidence of PNU-induced thymic lymphomas, was higher than that of F344 strain. The high level of DNA alkylation by PNU and the low activity of AGT in the thymus may contribute to the high incidence of thymic lymphoma in F344 rat.

Nephrotoxic effect of tris(2,3-dibromopropyl)phosphate on rat urinary metabolites: assessment from 13C-NMR spectra of urines and biochemical and histopathological examinations.

Rats received either single oral doses of 0, 25, 50, 100 and 200 mg/kg tris(2,3-dibromopropyl)phosphate (Tris-BP) or repeated doses of 50, 100 and 200 mg/kg/day Tris-BP for 7 days. Urine was collected over a 24-hr period and subjected to 13C-NMR and biochemical examinations. Tris-BP produced significant increases of urinary glucose and lactate. Urinary gamma-glutamyltransferase, lactate dehydrogenase and alkaline phosphatase levels were significantly elevated on the first 2 days of post-treatment. Histopathologically, the kidney exhibited proximal tubular damage at a dose of 200 mg/kg. There was a good correlation among the histopathological, biochemical results, and the 13C-NMR urinary metabolite fingerprints in the assessment of Tris-BP-induced renal damage. The abnormal patterns of metabolite excretion suggested that the lesions produced by Tris-BP were caused by changes in the metabolic function of tubular epithelial cells. The urinary excretion of lactate, enzymes and inhibition of glucose reabsorption from the tubular lumina may be attributed to necrosis and desquamation of the tubular cell.

Excretion, distribution and metabolism of 1,2,4-trichlorobenzene in rats.

1,2,4-Trichlorobenzene (TCB) labeled with C-14 was given perorally to rats at a dosage of 50 mg/kg for excretion and distribution studies. About 66% and 17% of the oral dose was excreted in the urine and feces, respectively, within 7 days. Trapped radioactivity in the expired air amounted to 2.1% of the dose, but production of labeled carbon dioxide was negligible. Tissue residues were evenly distributed throughout the organs and tissues examined, except for the adipose tissue which consistently had a little higher concentration. The urinary, fecal and expiratory metabolites were identified. Free 2,4,5- and 2,3,5-trichlorophenol (TCP) and their conjugates were mainly detected in the urine. 5- or 6-Sulfhydryl, methylthio, methylsulfoxide and methylsulfone derivatives of TCB were also detected as minor metabolites. Dichlorobenzenes and unchanged TCB were confirmed in the expired air. Reductive dechlroination seems to be catalysed by intestinal microflora enzymes.

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat.

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.