Acta pharmacologica et toxicologica最新文献

The metabolism of 4-14C-oestradiol in the rodent respiratory tract has been investigated in vitro. Using thin-layer radiochromatography, at least 3 and 2 metabolites were found at incubation with slices from the rat olfactory mucosa and lung, respectively. Autoradiography of the nasal region of rats injected intravenously with 4-14C-oestradiol showed a high level of radioactivity in the mucosa covering the respiratory region, and in the subepithelial parts of the olfactory mucosa. Autoradiography of rat and mouse lung slices incubated with 4-14C-oestradiol showed that a selective localization of radioactivity occurred in the bronchial mucosa. The radioactivity in the mucosa of the respiratory tract was reversibly bound and could be extracted with organic solvents.

In female and male mice the effect of exposure to trichloroethylene (TCE) seen at the lowest concentration is an increase in liver weight. The activity of plasma butyrylcholinesterase (BuChE) increases even more than the liver weight at corresponding concentrations, but only in the males. Depletion of testosterone through castration or destruction of the pituitary gland or hypothalamus, are the only other ways to experimentally induce corresponding increases in BuChE. Plasma BuChE activity increase was found to be a common reaction after exposure to TCE, perchloroethylene, chloroform, methylene chloride and carbon tetrachloride and also after exposure to ethanol. Other solvents such as toluene, xylene, benzene and 1,1,1-trichloroethane had little or no effect on BuChE activity. Normal and castrated male mice were continuously exposed for one month to 150 p.p.m. TCE. The increase in BuChE activity after the exposure was of the same magnitude as the increase seen after castration. BuChE activity in castrated males was not further increased by TCE exposure. Administration of testosterone with osmotic minipumps for 13 days almost restored the normal testosterone and BuChE levels in castrates. The effect of TCE exposure on BuChE activity in these animals was the same as on normal males. Testosterone levels were not influenced by the TCE exposure in normal males or in castrates given testosterone. No sex hormone binding globulins (SHBG) could be detected in the mice. BuChE activity changes induced through solvent exposure are therefore neither directly nor indirectly (through SHBG) due to effects on testosterone. The results from these animal experiments do not support the epidemiological findings of decreased testosterone levels in humans exposed to solvents.

The activity of coumarin 7-hydroxylase (coumarin 7-hydroxylation) was inhibited in B6 mouse liver after a single injection of methylglyoxal bis(guanylhydrazone (MGBG). The decrease in the activity in vivo was greatest (70%) one day after the drug injection and the hydroxylase activity in microsomal fraction prepared from livers of MGBG-treated B6 mice was still 25% decreased 5 days after the drug. The amount of cytochrome P-450 also was decreased in MGBG-treated livers with the same time-dependency as the inhibition of coumarin 7-hydroxylation. MGBG and its close derivative 1,1'-[methylethanediylidene)dinitrilo)bis(3-aminoguanidine) (MBAG) inhibited the activity in vitro of coumarin 7-hydroxylase, benzo(a)pyrene hydroxylase and 7-ethoxy 0-de-ethylase when microsomes were prepared from livers of untreated B6 mice. In every case MBAG was a better inhibitor than MGBG in vitro. The in vitro inhibition of MGBG of several drug metabolizing enzymes was not reversed when microsomes were preincubated with 1 mM putrescine, spermidine or spermine. These results suggest that the anti-cancer drug, MGBG, has a severe effect(s) on the drug metabolizing system at concentrations reached during the treatment of patients with MGBG.

It has been possible to sensitize the rat urethra without cutting its nerves. This was achieved by hypertrophy or disuse. Hypertrophy of the urethra (2-4-fold weight increase) was caused by the presence of an intraluminal paraffin bolus. Disuse was caused by diverting the flow of urine from the lower urinary tract. When examined in vitro after an experimental period of 1 to 4 weeks the EC50 value of the parasympathomimetic drug methacholine was in both cases half of that of controls. The common cause of the development of supersensitivity in the two types of experiments is thought to be decreases in the local concentration of transmitter at the muscle cells. The present findings favour the idea of a parasympathetic motor control of the rat urethra.

The effects of low-dose administration of the organophosphate cholinesterase inhibitors, soman, sarin and tabun, on growth rates over 85 days were studied in rats. Acetylcholinesterase (AChE) activity was determined in the striatum and the remainder of the brain 24 hrs following the last exposure to these agents. Further, the cumulative mortality of daily administration of several doses of soman, sarin and tabun for 25 days was studied. The animals treated with 25 micrograms/kg of soman or sarin for 85 days demonstrated reduced growth rates which returned to control levels after 30 days. The animals which received 50 micrograms/kg of sarin also grew at reduced rates which returned to control levels after 35 days, while the tabun-treated (100 micrograms/kg) animals required 38 days to return to control growth rates. The striatal AChE activity of the soman-treated group was reduced to 36% of control while the AChE activities of the high-dose sarin-treated group were reduced to 66% of control. The striatal AChE activity of the tabun-treated group was only 13% of control. It is suggested that growth rates may be used to monitor the development of tolerance to low-dose administration of organophosphate cholinesterase inhibitors.

The effect of pretreatment with the noradrenaline neurotoxin, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), upon the analgesia induced by various doses of 5-hydroxytryptamine (5-HT) was examined in rats and mice. DSP4 treatment (2 X 50 mg/kg, intraperitoneally) of rats caused a complete blockade of 5-HT induced analgesia in the tail-flick, hot-plate and shock titration tests. DSP4 treatment (1 X 50 mg/kg, intraperitoneally) of mice caused a partial blockade of 5-HT induced analgesia in the hot-plate test, but no significant blockade in the tail-flick test. These results are discussed with regard to serotonergic-noradrenergic interactions and the species discrepancy in nociceptive testing.

The potency of halogenated methanes to inhibit uptake of 5-hydroxytryptamine (5-HT) from the pulmonary circulation was studied using an isolated, perfused and ventilated rat lung preparation. The agents were vaporized and mixed with the inlet air. The results indicate that the degree of chlorination is the most important factor for potency of the methanes to inhibit lung uptake of 5-HT. When hydrogen was substituted with fluorine the potency was decreased dramatically. Bromine seemed to have the opposite effect. The data also suggested that the degree of chlorination was more important rather than hydrophobic/hydrophilic balance of the solvent molecule. These effects seem to be correlated with the narcotic effects of the substances studied.