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PubMed1975

Differential hydrolysis of bovine parathyroid hormone and its N-terminal peptide by rat kidney.

Highly purified bovine parathyroid hormone (b-PTH 1-84) and its synthetic N-terminal peptide (b-PTH 1-34) were labelled with 125-I and incubated with rat kidney homogenate at 37 degrees C for 1 hour to assess the degree of hydrolysis of the iodinated peptides through measurement of the increase of trichloroacetic acid soluble 125-I fraction. Rat kidney homogenate rapidly hydrolyzed b-PTH 1-84 but was scarcely effective in hydrolyzing b-PTH 1-34. When 125-I labelled b-PTH 1-84 and b-PTH 1-34 were injected intravenously in rats, hydrolysis in vivo of the former appeared to be much more rapid than that of the latter, as shown by the faster disappearance from plasma of trichloroacetic acid precipitable fraction. Incubation of b-PTH (1-84) with rat kidney homogenate caused a shift of 125-I PTH peak almost to the position of salt peak, while the position of 125-I b-PTH (1-34) was almost unchanged by incubation with rat kidney homogenate. N-terminal peptide of bovine parathyroid hormone thus appears to be less susceptible to hydrolytic degradation by rat tissue than the intact hormone, with resultant longer retention in the blood stream.

Animals↗

PubMed1992

A mechanism for the development of Clara cell lesions in the mouse lung after exposure to trichloroethylene.

Female CD-1 mice exposed to trichloroethylene (6 h/day) at concentrations from 20-2000 ppm developed a highly specific lung lesion after a single exposure, characterised by vacuolation of the Clara cells, the number of cells affected increasing with increasing dose level. At the highest dose levels pyknosis of the Clara cells was apparent. After 5 days of repeated exposures the lesion had resolved but exposure of mice following a 2-day break resulted in recurrence of the lesion. The changes in mouse lung Clara cells were accompanied by a marked loss of cytochrome P-450 activities. No morphological changes were seen in the lungs of rats exposed to either 500 or 1000 ppm trichloroethylene. Isolated mouse lung Clara cells were shown to metabolize trichloroethylene to chloral, trichloroethanol and trichloroacetic acid. Chloral was the major metabolite. Trichloroethanol glucuronide was not detected. In comparative experiments using mouse hepatocytes the major metabolites were trichloroethanol and its glucuronide conjugate. The activity of UDP-glucuronosyltransferase was compared in mouse lung Clara cells and hepatocytes using two phenolic substrates and trichloroethanol. Hepatocytes readily formed glucuronides from all three substrates whereas Clara cells were only active with the two phenolic substrates. The three major metabolites of trichloroethylene, chloral, trichloroethanol and trichloroacetic acid were each dosed to mice and of these metabolites, only chloral had an effect on mouse lung causing a lesion (Clara cell) identical to that seen with trichloroethylene. It is proposed that the failure of Clara cells to conjugate trichloroethanol leads to an accumulation of chloral which results in cytotoxicity. The known genotoxicity of chloral suggests that this lesion may be related to the development of lung tumours in mice exposed to trichloroethylene by inhalation.

Animals↗

PubMed1980

Studies of the integrity of iodinated bovine albumin after circulating in vivo.

The integrity of 125 I BSA circulating in vivo was assessed by immunoprecipitation, antibody binding, and sephadex chromatography. 125 I BSA measurements obtained by precipitation in trichloroacetic acid agreed closely with measurements obtained by antibody binding and immuno - precipitation for up to 12 days after injection or until 99.5% of the 125 I BSA was eliminated. The molecular weight of the circulating 125 I, after dissociation of immune complexes, was identical to non-labelled BSA. 99.5% of the BSA was eliminated from the circulation 10 to 15 days after injection. After this time 45% of the circulating 125 I which precipitated in trichloroacetic acid was not bound to BSA.

Animals↗

PubMed1986

Evidence for the existence of covalent nucleotide-thymidylate synthase complexes, identification of site of attachment, and enhancement by folates.

The formation of covalent binary complexes of thymidylate synthase and its nucleotide substrate dUMP, product dTMP, and inhibitor, 5-fluorodeoxyuridylate (FdUMP) was investigated using the trichloroacetic acid precipitation method. It was observed that, in addition to FdUMP, both dUMP and dTMP were capable of covalent interactions with the enzyme in the absence of added folates. The presence of folate, dihydrofolate, or tetrahydrofolate (H4folate) was found to produce substantial enhancements in the covalent binding of both FdUMP and dUMP to the enzyme with H4folate being the most effective agent. Further, covalent binary complexes of the enzyme with the three radiolabeled nucleotides were isolated by trichloroacetic acid precipitation and subjected to CNBr cleavage. The active-site CNBr peptide was isolated by reverse phase high performance liquid chromatography, and the first five N-terminal amino acid residues were sequenced by the dansyl-Edman procedure. Each active site peptide obtained from the covalent binary complexes as well as that from the covalent inhibitory ternary complex formed from enzyme, FdUMP, and 5,10-methylene-H4folate exhibited an identical sequence of Ala-Leu-Pro-Pro-(X)-, and the 5th amino acid was found to be associated with radiolabeled nucleotide ligand. Dansyl-Edman sequence analysis of the active site CNBr peptide, derived from enzyme which had been treated with iodoacetic acid, gave a sequence of Ala-Leu-Pro-Pro-CmCys (where CmCys is carboxymethylcysteine), thus confirming the fact that the fifth residue from the N terminus is Cys-198. In all the cases, the active site Cys-198 residue was found to be covalently linked to the nucleotides. These results provide unequivocal proof that the covalent binary complexes of enzyme with dUMP and dTMP predicted in the catalytic reaction mechanism actually exist.

Deoxyuracil Nucleotides↗

PubMed1975

New inhibitors of methane production by rumen micro-organisms. Development and testing of inhibitors in vitro.

1. A procedure is described for assaying in vitro the activity of various inhibitors of methane production by rumen micro-organisms. 2. Methods of preparation of various inhibitors are described together with attempts to characterize these compounds by determining their physical properties (physical state, density, chromatographic behaviour), their hydrolysis by rumen contents and their relative potency as inhibitors. 3. The results of preliminary studies with trichloroethanol and its ester with pivalic acid are given. 4. The inhibitory activities of several groups of related compounds are reported. These include the polyhalogenated alcohols and their esters with pivalic acid, the esters of trihalogenated alcohols and monobasic fatty acids from C2 and C16 and the trihalogenated alcohol esters of dibasic acids. The results of experiments with esters of alcohols and polyhalogenated carboxylic and sulphonic acids are also given. 5. It is concluded that the mechanism of action of the inhibitors might be similar to that of known polyhalogenated methane analogues (e.g. chloroform). The relative activity of various compounds might be partly governed by the ease of their absorption into the microbial cells and by the extent to which the esters can be hydrolysed by rumen contents. 6. The results show that some substances are very poor inhibitors, unless they are esterified (e.g. trichloroacetic acid) but on the whole the esters in which the polyhalogen grouping is on the alcohol portion of the molecule are better inhibitors than those in which it is on the acid portion of the molecule.

Animals↗

PubMed2005

Effect of sonication on the photo-catalytic mineralization of some chlorinated organic compounds.

Effects of the irradiation of ultrasound (US) on the photo-catalytic mineralization of some chlorinated organic compounds such as dichloroethane, tri- and tetrachloroethylenes, chloroacetic acids and chloromethanes were examined in oxygen saturated aqueous solutions suspended titanium dioxide (P25) particles. The yields of the sonochemical mineralization for these compounds were found to be extremely low compared to the photo-catalysis. However, the pre-sonication, US irradiation on the sample solution before the photo-irradiation, enhanced significantly the following photo-catalytic degradation to the complete oxidation. The effect was investigated in detail and it was found that the effect was mainly owing to the increase in the capability of the catalysis of which particles were sparsely dispersed by the sonication. The other contribution of the pre-sonication effect was found to be "pre-sonolysis", the initial formation of some intermediated products sonochemically, which are oxidizable more rapidly further to carbon dioxide than the original compound by the following photo-catalytic reactions. The pre-sonolysis effect was observed remarkably for trichloroacetic acid and tetrachloromethane, both of which are known to be hardly reactive to the photo-catalytic degradation. The photo-catalytic degradation with simultaneous sonication were also carried out for these compounds. The synergetic effect in the mineralization was observed both for carbontetrachloride and for trichloroacetic acid, the higher carbon dioxide yield being obtained in the simultaneous reaction than the sum of the yields in the photo-catalysis and the sonolysis each alone, while no significant synergetic effect was observed in the mineralization of other compounds.

Journal Article↗

PubMed1983

Methodological aspects on the firefly luciferase assay of adenine nucleotides in whole blood and red blood cells.

The firefly luciferase assay of adenosine-5'-triphosphate (ATP) is used in a simple procedure for the determination of adenine nucleotides in whole blood and red blood cells. Cells are lysed with cold trichloroacetic acid and nucleotides are determined in the lysate after dilution with buffer. In a comparative study with the spectrophotometric assay of ATP, extracts were prepared by centrifugation of the lysate to remove interfering turbidity. This step resulted in a significant loss of ATP in the clear supernatant. This loss could be avoided by determination of ATP by the firefly luciferase assay in diluted uncentrifuged lysates. The yields of ATP, ATP + ADP and ATP + ADP + AMP were compared in a red blood cell preparation after lysis with trichloroacetic acid and another lytic method based on the detergent triton X-100. The precision was better with acid whereas yields were essentially the same with both methods. The method of standardization, external or internal, was of little practical importance regarding yields and precision, but internal calibration is recommended to ensure that there is no interaction of the luciferase reaction with lytic reagent or sample.

Adenosine Diphosphate↗

PubMed1995

Considerations concerning the murine hepatocarcinogenicity of selected chlorinated hydrocarbons.

Of the chlorinated hydrocarbons discussed above, all six are associated with induction of hepatocellular neoplasia in mice. None of the six is considered to be potent mutagen and most are without any significant genotoxic activity as assessed by conventional in vitro testing schemes. Although some of the agents have biological effects in common (see Figure 4), there is no single biological response (mode of action) that they all share to provide a mechanistic basis for the observed murine hepatocarcinogenicity. Based upon the information currently available for each of the chlorinated hydrocarbons discussed above, it is probable that some modes of action may be more contributory to the rodent carcinogenic response than others; however, no mode of action, pathway, or mechanism should be considered to be mutually exclusive. The murine hepatocarcinogenic effect of TriCE is most probably contingent upon its species-specific metabolism to trichloroacetic acid and DCA. There is fairly consistent evidence that cytotoxicity and reparative hyperplasia are associated with doses of TriCE that cause induction of liver neoplasms. The possibility that peroxisome proliferation is playing a role in the induction of mouse hepatocellular neoplasia remains a tempting explanation, since higher intracellular steady states of H2O2 production would be consistent with observed enhanced cellular proliferation as well as the possibility of in vivo DNA damage. The mouse hepatocarcinogenicity associated with TetCE most probably is associated with species-specific metabolic production of trichloroacetic acid. As with TriCE, cytotoxicity and reparative hyperplasia may represent a potential mode of action for the observed hepatocarcinogenicity. Once again, the potential for enhanced peroxisome proliferation is consistent with enhanced cell proliferation and oxygen radical damage would help explain the random point mutations in ras proto-oncogenes documented in DNA from TetCE-induced mouse liver tumors. DCA-induced mouse hepatocellular neoplasia is probably influenced by cytotoxicity and reparative hyperplasia, but there is also recent evidence that DCA may directly damage DNA, implying an in vivo genotoxic mechanism may be operational. Likewise, altered expression of several genes suggests that subversion of signal transduction may play a role in the induction or progression of liver tumor development. As with TetCE and TriCE, a role for peroxisome proliferation is still a consideration, although the liver tumor response is obvious at doses too low to cause peroxisome proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1975

Enzymatic synthesis of a blood group H-related glycosphingolipid by an alpha-fucosyltransferase from bovine spleen.

An alpha-fucosyltransferase activity has been detected in a purified membrane preparation isolated from bovine spleen which catalyzes the transfer of L-fucose from GDP-L-[14C]-fucose to a tetraglycosylceramide (Lac-nTet-cer, Galbetal-4GlcNAcbeta1-3Galbeta1-4-Glc-cer) to form the blood group H-related glycosphingolipid. The membrane preparation contained a highly active endogenous nonlipid acceptor, which could be precipitated by 5% trichloroacetic acid or chloroform-methanol-water (6:3:5, v/v/v), whereas there was little endogenous glycosphingolipid acceptor. The optimum pH value for the incorporation of L-fucose was 6.4 in cacodylate-HCl buffer. The Km values were 0.6 mM and 0.36 mM for Lac-nTet-cer and GDP-L-fucose, respectively. The 14C-labeled product of the reaction was isolated and purified; it migrated with human erythrocyte blood group H-active pentaglycosylceramide. the terminal [14C]fucose was hydrolyzed 85% and 55% by 0.1 N trichloroacetic acid at 100 degrees for 2 hours and Charonia lampas alpha-fucosidase (19 hours at 37 degrees), respectively. The 14C-labeled product inhibited the hemagglutination reaction of O-type cells against eel anti H(O) globulin and formed a precipitin line with Ulex europeus lectin.

Animals↗

PubMed1980

Stimulatory activity of serum on prolactin production by human decidua.

Fetal calf serum (FCS) enhances the synthesis and secretion of prolactin (PRL) by explants of human decidua incubated in Gey's balanced salt solution. In order to further characterize the factors involved in the prolactin-stimulating activity (PSA) of serum, decidua was incubated in Gey's buffer alone and in buffer containing either FCS, bovine serum albumin (BSA), or human serum (HS). When buffer was supplemented with varying concentrations of FCS, ad dose-related PSA was apparent between 0.1% and 10%. The PSA of FCS was not altered by eithr heating (85degrees C for 30 minutes), boiling, or dialysis. The protein fraction of FCS, precipitated with trichloroacetic acid, redissolved in dilute NaOH, and dialyzed against Dulbecco's phosphate buffer, demonstrated PSA comparable to that of whole serum. A similar concentration of BSA added to Gey's buffer did not stimulate the production of PRL by decidua. The PSA of human serum obtained from euprolactinemic men and women was not different from that of FCS. These data indicate that FCS and HS contain a substance(s) (1) which stimulates the secretion of PRL by human decidua, (2) which is very stable, being resistant to dialysis, boiling, and denaturation by trichloroacetic acid, (3) and which is most likely a large polypeptide with a molecular weight greater than 12,000 or a smaller moiety tightly bound to a protein.

Animals↗

PubMed1981

Hormonal stimulation of eucaryotic cell ADP-ribosylation.

The effect of thyrotropin (TSH) on the ADP-ribosylation of endogenous thyroid cell acceptor proteins was examined. Cells were "permeabilized" at 4 degrees C in hypotonic medium and then exposed to [(32)P]- or [(3)H-adenine]NAD(+). The net incorporation of labeled ADP-ribose was measured by trichloroacetic acid precipitation. TSH (100 mU/ml) enhanced ADP-ribosylation with a maximum effect after 30-60 min in the majority of experiments. TSH stimulation was observed even when the incubation contained 1,000-fold more exogenous NAD(+) than the amount of NAD(+) contributed by the permeabilized cells, indicating an effect on enzymatic activity rather than an alteration in NAD(+) pool size or specific activity. No incorporation of radioactivity from labeled NAD(+) was observed in cells not rendered permeable to NAD(+) by hypotonic shock. TSH did not increase the rate of disappearance of trichloroacetic-precipitable radioactivity and did not contain intrinsic NAD(+) glycohydrolase activity. Alkali and snake venom phosphodiesterase, but not ribonuclease or deoxyribonuclease digestion of trichloroacetic acid precipitable thyroid cell radioactivity, revealed primarily 5'-AMP, consistent with an effect of TSH on mono-ADP ribosylation. Nicotinamide and thymidine (50 mM) inhibited both basal and TSH-stimulated ADP-ribosylation of thyroid cell protein. Dibutyryl cyclic (c)AMP (0.1 mM) inhibited endogenous ADP-ribosylation by approximately 35% but had no effect at lower concentrations. 0.5 mM isobutylmethylxanthine inhibited this reaction by approximately 60%. We suggest that TSH enhances thyroid cell ADP-ribosylation by a mechanism independent of cAMP as a second messenger, and that ADP-ribosylation plays a role in the expression of TSH.

Adenosine Diphosphate Ribose↗

PubMed1998

Metabolism of chloral hydrate in mice and rats after single and multiple doses.

Chloral hydrate is a hepatocarcinogen in mice but not rats. To examine this species-related difference, male and female B6C3F1 mice and Fischer (F344) rats were treated by gavage with 1 or 12 doses of chloral hydrate, and concentrations of the drug and its metabolites were determined in plasma at 0.25, 7, 3, 6, and 24 h and 2, 4, 8, and 16 d after the last treatment. Maximum levels of chloral hydrate were observed at the initial sampling time of 0.25 h. By 1 h, levels dropped substantially, and by 3 h, chloral hydrate could not be detected. Trichloroacetic acid was the major metabolite found in the plasma, with peak levels being observed 1-6 h after dosing. The concentrations then slowly decreased such that by 2 d this metabolite could no longer be detected. Trichloroethanol was assayed as both the free alcohol and its glucuronide. Maximum levels of trichoroethanol occurred at 0.25 h, and by 1-3 h approached the limits of detection. A pharmacokinetic model was constructed to describe the metabolic data. The plasma half-life values of chloral hydrate were similar in both species. In mice, the rate of elimination of trichloroacetic acid was significantly increased after multiple doses; this difference was not observed with rats. The half-life of trichloroethanol and its glucuronide was significantly greater in rats as compared to mice. None of the metabolic parameters appears to account for the hepatocarcinogenicity of chloral hydrate seen in mice but not rats.

Animals↗

PubMed1970

Agar-Gel Precipitating Antibody in Pseudomonas aeruginosa Infections.

The human immune response to Pseudomonas aeruginosa infection was studied by using the double diffusion in agar-gel technique. Antigens from Fisher-Devlin-Gnabasik immunotypes were prepared by both trichloroacetic acid extraction and ultrasonic disruption. Serum from 72 of 168 patients (43%) from whom P. aeruginosa was isolated formed from one to eight precipitin bands. Precipitins were demonstrated in the sera of 60 of 66 (91%) patients recovering from bacteremia and deep infections; however, they were usually absent when Pseudomonas infection was fatal or when there was no clinical evidence of significant infection. Precipitating antibody was detectable at serum dilutions as high as 1:32, and appearance of single bands correlated with hemagglutinating antibody titers of >/=1:128. Antigen from sonically disrupted organisms usually resulted in stronger precipitin bands than trichloroacetic acid extracts, and antigen from the homologous infecting strain occasionally increased test sensitivity. None of 50 normal controls had Pseudomonas precipitins as was the case in patients convalescing from Escherichia coli (15 patients), Klebsiella-Enterobacter-Serratia (18), and Proteus (14) bacteremias. Measurement of agar-gel precipitins was useful and specific in evaluating the circulating antibody response to P. aeruginosa infections.

Journal Article↗

PubMed1993

Studies of 5-fluorodeoxyuridine 5'-monophosphate binding to carboxypeptidase A-inactivated thymidylate synthase from Lactobacillus casei.

The binding of 5-fluorodeoxyuridylate (FdUMP) to carboxypeptidase-inactivated thymidylate synthase obtained from methotrexate-resistant Lactobacillus casei was investigated using [3H]FdUMP in a trichloroacetic acid precipitation assay and by 19F nuclear magnetic resonance spectroscopy. The cleavage of 1 valine residue from the carboxyl terminus of one of the identical subunits of the enzyme dimer correlates with complete loss of thymidylate synthesis (Aull, J. L., Loeble, R. B., and Dunlap, R. B. (1974) J. Biol. Chem. 249, 1167-1172). We have further investigated the phenomenon of carboxypeptidase A-dependent inactivation of thymidylate synthase by employing immobilized carboxypeptidase A in order to facilitate the isolation and characterization of the inactivated enzyme. The time course of carboxypeptidase treatment of thymidylate synthase has been profiled by the spectrophotometric assay, tritium release assay, trichloroacetic acid precipitation assay (covalent adduct analysis), 19F nuclear magnetic resonance spectroscopy, and amino acid analysis. The techniques utilized in this study yielded results which showed that the completely inactivated enzyme (failure to catalyze thymidylate formation) continued to catalyze both covalent FdUMP-enzyme interactions and the formation of the covalent inhibitory ternary complex with the cofactor, 5,1O-methylenetetrahydrofolate, although to a reduced extent, thus effectively uncoupling these processes from thymidylate synthesis activity.

Binding Sites↗

PubMed1989

The effect of chlorinated chemicals on porphyrin metabolism--the synergistic effect with chlorinated chemicals and low concentrations of griseofulvin.

The synergistic effect of chlorinated chemicals and 0.1% griseofulvin on porphyrin metabolism was investigated. Feeds containing 0.1% 4-chloro-m-cresol, 0.1% cumarone or 0.25% trichloroacetic acid with or without 0.1% griseofulvin were given to dd-y strain mice respectively. The treatments were continued for 10 to 450 days, after which coproporphyrin and protoporphyrin in the erythrocytes and liver were analyzed. In the 0.1% griseofulvin alone group, protoporphyria was induced in 6 of 55 dd-y strain mice, although the other 49 mice did not show any abnormal porphyrin metabolism and the severity of the protoporphyria was mild in the 6 mice. In the 4-chloro-m-cresol group, a slight elevation of erythrocytic porphyrins was seen, but the difference was not statistically significant. Elevation of the hepatic porphyrins was not seen. Trichloroacetic acid and cumarone did not influence porphyrin metabolism, and also there was no synergistic effect of griseofulvin on porphyrinopathy. These results suggest that the three chemicals selected in this study are not capable of inducing porphyrinopathy.

Animals↗

PubMed1981

Distribution of radiomanganese in the rumen of sheep.

Twelve sheep, each prepared with a rumen fistula, were divided into three groups of four and fed three dietary levels of manganese (22,300, and 3000 micrograms/g dry matter) for 11 weeks. The sheep were then dosed with radioactive manganese and samples of rumen contents were taken via the rumen fistula at 1, 7, and 13 h after dosing. The sheep were immediately killed after the last sampling and total rumen contents were mixed and sampled. Rumen fluid was separated frm all samples and fractionated by centrifugation into protozoa plus plant particles, bacteria, and cell-free fraction. The bacterial cells were disrupted and fractionated into cell walls and cytoplasm. The cytoplasmic protein was precipitated with trichloroacetic acid. Although the centration of radiomanganese in rumen fluid decreased with time after dosing from 14.4--17.8 to 6.1--9.3% of dose/L the protozoal and bacterial uptakes of radiomanganese were not significantly different and ranged from 26.5 to 40.6% and 18.9 to 31.7% of total in the rumen fluid, respectively. There was also no effect of dietary concentration of manganese on the uptake and distribution of radiomanganese in the rumen fluid fractions. However, on the average more radiomanganese was found in the bacterial cell walls (48.1--75.3% of total in bacteria) and less in the cytoplasm (51.9--24.7% of total in bacteria) with increasing dietary manganese. Very little radioactivity was found in the trichloroacetic acid precipitated cytoplasm (1.79--0.78% of total in cytoplasm). concentrations of manganese in the bacteria and bacterial cell walls were higher than, and closely related with, those in the diet. Specific activities of radiomanganese decreased in all fractions with increasing dietary manganese. Approximately 15--17% of the total radiomanganese in the rumen contents at 13 h after dosing was found in the protozoal fraction and 10--15% was found in the bacterial fraction; only approximately 21% of the radiomanganese remained in cell-free fraction of the rumen fluid in each dietary treatment.

Animals↗

PubMedDate not supplied

Selective and sensitive determination of pamidronate in human plasma and urine by gas chromatography with flame photometric detection.

A rapid, selective and sensitive method for the determination of pamidronate in human plasma and urine samples by gas chromatography (GC) has been developed. After deproteinization of the sample with trichloroacetic acid, pamidronate was converted into its N-isobutoxycarbonyl methyl ester derivative and measured by GC with flame photometric detection (FPD), using a HP-1 capillary column. The derivative preparation and GC analysis were accomplished within 30 min. The derivative was sufficiently volatile and stable, giving a single and symmetrical peak, and provided an excellent FPD response. The detection limit of pamidronate, at a signal-to-noise ratio of 3, was ca. 100 pg injected, and the calibration curve for this compound in the range 20-1000 ng was linear and sufficiently reproducible for quantitative determination. This method could be successfully applied to plasma and urine samples without a preliminary clean-up except for deproteinization with trichloroacetic acid, and pamidronate could be measured without any influence from coexisting substances. Overall recoveries of pamidronate added to plasma and urine samples were 93-97%. The coefficients of variation for intra-assay and inter-assay of pamidronate in these samples were 1.0-7.9% (n = 3) and 4.1-8.3% (n = 6), respectively.

Chromatography, Gas↗

PubMed1976

Specifity and sensitivity of the inhibition of drug metabolism following inhalation of carbon disulphide-air mixtures.

A single 8-h exposure of adult female Wistar rats to 20 ppm carbon disulphide (CS2), the threshold limit value (TLV) in several countries, was sufficient to cause inhibition of the following drug-metabolizing reactions: formation of trichloroethanol and trichloroacetic acid from trichloroethylene (aliphatic C-hydroxylation), formation of 4-hydroxyantipyrine from antipyrine (quasi-aromatic C-hydroxylation), formation of acetaminophenol from acetanilid (aromatic C-hydroxylation) and phenacetin (oxidative odealkylation), respectively, and formation of 4-aminoantipyrine from aminopyrine (oxidative N-demethylation). The behaviour of these effects was dependent on the dose of CS2 administered in that the inhibitory process was enhanced when increasing the concentration to (50), 100, 200, and 400 ppm. The respective changes could be demonstrated by a short-duration (6-h) reduction in the urinary excretion of the metabolites. In the case of trichloroethylene the limitation in metabolite formation persisted for as long as 36 h due to the varying rate of formation of trichloroethanol and trichloroacetic acid. This deficiency in excretion was compensated in part during the subsequent elimination phase (up to 24 and 36 h, respectively), an observation which suggests the rapid reversibility of the alteration. As shown by the respective prolongation of the hexobarbital sleeping time in the rat, the side-chain oxidation of hexobarbital to ketohexobarbital was increasingly inhibited by rising concentrations of CS2 in the range of 20 to 400 ppm/8 h. On the basis of the present results it is concluded that CS2 also inhibits various oxygenases of the microsomal enzyme system. In adult female NMRI mice a significant inhibition of the microsomal procaine-hydrolyzing esterase of the liver was observed only after 400 ppm/8 h; however, this limitation did not affect the LD50 of procaine-HCl, particularly as the corresponding serum esterase activity also remained uninfluenced. The aromatic N-acetylation of sulphisomidine and the quasi-aromatic N-acetylation of 4-aminoantipyrine in rats failed to be significantly reduced by CS2 even after 400 ppm/8 h, nor did the same dose of CS2 affect the glucuronidation of 4-hydroxyantipyrine in the same animal species. It is concluded from the above results that the specificity and sensitivity of the inhibition of drug metabolism observed in small laboratory animals is probably similar to that prevailing in man. This assumption has already been substantiated for the oxidative N-demethylation of aminopyrine.

Acetanilides↗