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H M Bolt

Publications and source records attributed to H M Bolt.

At least 181 records · Page 10Linked to original sources
PubMed1982

Strain and species differences in the induction of ATPase-deficient hepatic foci by diethylnitrosamine.

Diethylnitrosamine (5 mg/kg) was intraperitoneally administered to rats, mice, guinea pigs and tupaias daily for 3 weeks. After 12 weeks of cessation, focal areas of ATPase-deficiency of hepatocytes appeared only in rats and, to a much lesser extent, in guinea pigs. Female rats were more sensitive than males and Wistar rats were less sensitive than Sprague-Dawley rats. These data show that quantitation of ATPase-deficient foci as a determinant of hepatocarcinogenicity is mainly restricted to the rat species.

Adenosine Triphosphatases↗
PubMed1982

Comparative pharmacokinetics of oestradiol, oestrone, oestrone sulfate and "conjugated oestrogens" after oral administration.

The time course of free oestradiol and oestrone as well as of total (free and conjugated) oestrone was determined in plasma of women after oral ingestion of 3.75 mg conjugated equine oestrogens, or 9.74 micromol of oestrone sulfate, oestrone, and oestradiol, respectively. All these oestrogen preparations led to transiently increased plasma oestrogen levels which fell to normal values after 48 h. The main difference observed between administration of free oestrone or oestradiol and of conjugated oestrogens (oestrone sulfate or equine oestrogens) was a much more protracted influx of oestrogens from the intestine into the plasma compartment, with a tendency to more sustained plasma levels, if conjugated oestrogens were administered. There was a consistent discontinuity in plasma oestrogen levels 10--12 h after oral ingestion of all the preparations examined indicating enterohepatic circulation. Comparison of "areas under the curve" obtained with the present preparations to similar previous studies on ethinyl oestradiol indicated that the bioavailability of the non-ethinyl oestrogens is by more than one order of magnitude less than that of ethinyl oestradiol after oral administration. The ratio of oestrone/oestradiol was the highest with free oestrone and similar among the other three preparations indicating an increased metabolism of sulfoconjugated oestrone to oestradiol after oral application when compared with free oestrone.

Administration, Oral↗
PubMed1981

Covalent binding of haloethylenes.

Halogenated ethylenes are metabolized to reactive intermediates which covalently bind to different cellular targets. Vinyl chloride and vinyl bromide metabolites bind to DNA, preferably to N-7 of deoxyguanosine. With RNA, 1,N6-ethenoadenosine and, 3,N4-ethenocytidine moieties are formed. All the haloethylenes in which this effect has been studied form metabolites capable of alkylating proteins, preferably at free sulfhydryl groups. Also, there is alkylation by haloethylene metabolites of cellular coenzymes. An observed increased exhalation of acetone by rats exposed to different haloethylenes can possibly be explained by alkylation of cytosolic coenzyme A. Such metabolic effects may serve as an indicator for reactive metabolite formation in vivo and should be more investigated.

Animals↗
PubMed1981

Inhalation pharmacokinetics based on gas uptake studies. III. A pharmacokinetic assessment in man of "peak concentrations" of vinyl chloride.

On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of "peak concentrations" of vinyl chloride, as occurring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed "linear" pharmacokinetics up to atmospheric exposures of 200-300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using "'steady-state-kinetics". After treating the processes of "influx", "efflux", and "metabolism", the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2h constant exposure to 5 ppm vinyl chloride and (b) two subsequent "peaks" of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would solely be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the "detoxifying" pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.

Animals↗
PubMed1981

Inhalation pharmacokinetics based on gas uptake studies. I. Improvement of kinetic models.

An improve pharmacokinetic model is described for inhalation of volatile xenobiotics from a closed gas phase system. This model is based on steady-state kinetics and covers metabolic elimination processes of either first-order, zero-order, or Michaelis-Menten characteristics. It is emphasized that the distribution of a volatile compound between gas phase and organism under steady-state conditions may be much different from a static equilibrium obtained in absence of metabolism, as it is observed after application of a metabolic inhibitor. A re-analysis or previous experimental data on dose-dependent pharmacokinetics of different haloethylenes reveals that, in general, the metabolic elimination processes of the rapidly equilibrating mono-haloethylenes (and vinylidene fluoride) can be resolved with excellent accuracy into sections of first-order and zero-order kinetics. Other compounds show a more smooth transition from first-order elimination (at lower atmospheric concentrations) into conditions of saturation (dichloroethylenes, trichloroethylene). The analyses are consistent with a recent concept of Andersen (1980) that metabolic elimination of inhaled xenobiotics is limited by either the capacity of metabolic enzymes or factors of transport to the metabolic sites.

Animals↗
PubMed1981

Inhalation pharmacokinetics based on gas uptake studies. II. Pharmacokinetics of acetone in rats.

Inhalation pharmacokinetics of acetone in rats was studied using gas uptake techniques. Under conditions of negligible metabolism (saturation of metabolizing enzymes) the coefficient of distribution Keq between organism and gas phase was 220 which confirmed that acetone is mainly (but not exclusively) distributed within the body water compartment. The metabolic elimination of acetone from the animals followed strict Michaelis-Menten saturation kinetics; the km corresponded to 160 ppm in the atmosphere, Vmax was 230 mumol x h(-1) x kg(-1). A shift in the distribution pattern of acetone under conditions of prevalent metabolism was theoretically predicted and experimentally proven; as the partial process of metabolic elimination was dose-dependent, this "depleted" the animal compartment from acetone in a dose-dependent fashion causing a shift in the "steady-state-constant", Kst. Part of the acetone which was metabolically eliminated (4.7%) appeared in the urine as formate within 7 days after ending a 48-h exposure to acetone; this excretion was linear with time. The data suggested existence of a formate pool in the organism from which formate was released with delay. Hence, limitations may be inferred as to the applicability of urinary formate excretion as a quantitative indicator for changing conditions of acetone exposure.

Acetone↗
PubMed1981

DNA alkylation by vinyl chloride metabolites: etheno derivatives or 7-alkylation of guanine?

The state of the literature led to a re-investigation of the alkylation products caused by vinyl chloride metabolites in DNA. When rat liver microsomes, an NADPH-regenerating system, DNA and [14C]vinyl chloride were incubated and, when the DNA was subsequently re-isolated and (enzymatically) hydrolyzed, chromatograms (on Aminex A-6) showed the presence of 1,N6-ethenodeoxyadenosine, 3,N4-ethenodeoxycytidine and 7-N-(2-oxoethyl)guanine (the product of hydrolysis of 7-N-(2-oxoethyl)-deoxyguanosine). By contrast, when rats were exposed to [1,2-14C]vinyl chloride and when the liver DNA of these rats was subjected to similar procedures, no radioactive 'etheno' derivatives could be detected, but a radioactive peak was eluted with 7-N-(2-oxoethyl)guanine. This peak could be transformed into 7-N-(2-hydroxyethyl)guanine; the chromatographic behaviour of which was identical to the reference compound used by Ostermann-Golkar et al. (Biochem. biophys. Res. Commun., 76 (1977) 259). Thus, it is concluded that the compound described by these authors, 7-N-(2-oxoethyl)guanine is in fact the major product of base alkylation in DNA after exposure to vinyl chloride.

Alkylation↗
PubMed1981

Interaction of acrylonitrile with hepatic microsomes of rats and men.

Acrylonitrile (AN) showed spectral interaction with hepatic microsomes from mouse, rat and man. Whereas human and rat liver microsomes resulted in ligand AN-binding spectra, mouse liver microsomes behaved differently. Hepatic microsomes from phenobarbital-treated mice with AN showed a type I substrate binding; ligand spectra are recorded with microsomes from benzo[a]pyrene-treated mice. Microsomes from untreated control mice showed a mixed type behaviour.

Acrylonitrile↗
PubMed1981

Irreversible protein binding of acrylonitrile.

1. After i.p. injection of [2,3-14C]acrylonitrile to rats, a significant portion of radioactivity becomes irreversibly attached to proteins of liver, lung, spleen and other tissues. 2. When rat liver microsomes were incubated with [2,3-14C]acrylonitrile, a time-dependent irreversible binding of radioactivity occurred to microsomal proteins. This binding was not dependent on NADPH. A high extent of binding to heat-inactivated microsomes indicated that no enzymic metabolic step was involved. 3. The irreversible binding of [2,3-14C]acrylonitrile to rat liver microsomal protein in vitro was inhibited by thiols (cysteine, glutathione, mercaptoethanol). The greatest inhibitory potency was displayed by dithiocarb (diethyl dithiocarbamate).

Acrylonitrile↗
PubMed1981

Intestinal first-pass effects of estrone sulfate and estrone in the rat.

Mixtures of (14C)-estrone and (3H)-estrone-sulfate (10 micrograms and 13 micrograms, respectively) were instilled into the lumina of intact jejunal loops of rats. Estrone was faster absorbed into portal blood than was estrone-sulfate (72% vs. 17% in 30 min). In portal blood the chemical forms derived from estrone were: unchanged estrone (72%), estrone-glucuronide (14%), estrone-sulfate (5%) and estradiol (9%); no estriol was formed. The chemical forms of estrone sulfate were: estrone-sulfate (86%), estrone (6%), estrone-glucuronide (2%), estradiol (2%) and estradiol-sulfate (4%). These metabolites were also found in the lumen. It is concluded that the intestinal first-pass effects do not significantly influence the hormonal activities of the two estrogens.

Animals↗
PubMed1980

Binding kinetics of vinyl chloride and vinyl bromide at very low doses.

Vinyl chloride and vinyl bromide are metabolically activated by liver microsomal enzymes to intermediates that covalently bind to proteins and nucleic acids. Several lines of evidence suggest the involvement of the epoxides, i.e., chloroethylene oxide or bromoethylene oxide. Proven targets for alkylation are adenine, cytosine and guanine moieties in nucleic acids, and sulfhydryl groups of proteins. For all the halogenated ethylenes studied so far, including vinyl chloride and vinyl bromide, metabolism in vivo is a dose-dependent, saturable process. The metabolic capacity of rats is saturated at atmospheric concentrations of 250 ppm vinyl chloride and 55 ppm vinyl bromide. As recent reports describe a diminishment of hepatocellular glutathione in rats after exposure to vinyl chloride concentrations of 50 ppm and more, we carried out a series of experiments measuring covalent binding of vinyl chloride metabolites after exposure to different concentrations of 14C-vinyl chloride. In all of these experiments, including one of an exposure to only 2 ppm vinyl chloride, hepatic covalent protein binding was related to the dose of vinyl chloride which was actually metabolized, and the ratio between bound and metabolized material was constant. This strongly suggests that hepatic glutathione levels must have only a very limited impact on covalent protein binding of vinyl chloride metabolites, an assumption which is supported by a lacking effect of a pretreatment with diethylmaleate. A scheme of hepatocellular compartimentation of metabolic steps is proposed which serves to explain these findings.

Alkylation↗
PubMed1980

Covalent binding of drug metabolites to DNA--a tool of predictive value?

The presently available data suggest at least some correlation between covalent binding of drug metabolites to DNA and carcinogenicity of that drug. More data, however, are needed to establish the predictability of covalent DNA binding assays for extrahepatic cancer. A covalent binding assay requires administration of radioactively labelled compound to the experimental animals; the availability of labelled compound and requirements as to radiochemical purity, chemical and biochemical stability are limiting the applicability of this procedure. Many technical pitfalls accompany covalent DNA binding assays. It is concluded that at the present time DNA binding assays do not represent routine procedures within a standard test battery for carcinogenicity, but are invaluable for more in-depth research which probably follows routine testing.

Animals↗
PubMed1980

Characteristics of haloethylene-induced acetonemia in rats.

A series of halogenated ethylenes (vinyl chloride, vinylidene fluoride, cis- and trans-1,2-dichloroethylene, perchloroethylene) induces increased acetone exhalation in rats. Exposures of differently pre-treated rats to vinylidene fluoride suggest that a metabolite of the haloethylene must be envolved in eliciting this formation of acetone. This conclusion is based on (a)dependence of acetone exhalation on the concentration of vinylidene fluoride, (b)effect of inducing agents, (c)effect of pyrazol, a metabolic inhibitor, (d)effect of cysteine, (e)effect of hypoxia and (f)the time course of acetone exhalation.

Acetone↗
PubMed1980

The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women.

Plasma levels of ethynylestradiol (EE), EE sulphate (EES), EE glucuronide (EEG) and prolactin were measured in women up to 72 h following the oral administration of 3 mg of EE. The decline in plasma EE levels showed a sharp discontinuity at 10 h which is assumed to be due to the beginning of enterohepatic circulation (EHC). After this event, an apparently terminal monoexponential decline was eventually established with a half-life of 13.1 h. As a result of EHC, the volume of distribution was increased by 60% to 6.0 1.Kg-1 but it does not appear that any significant accumulation of EE would occur during multiple dosing. Plasma levels of EES were, on average, 22.5 times greater than those of EE and this circulating metabolite may act as a reservoir of EE. No circulating EEG could be detected. Comparing these results with those previously obtained with 50 microgram EE, there was no evidence of dose dependency in the pharmacokinetics of this steroid. Plasma prolactin levels were markedly enhanced by this single dose of oestrogen.

Adult↗
PubMed1980

Pharmacokinetics of vinyl chloride in the Rhesus monkey.

The metabolic elimination of vinyl chloride in Rhesus monkeys is a dose-dependent, satruable process, as in rats. Below 200-300 ppm of vinyl chloride (VC) in atmosphere, elimination obeys a first-order law; the clearance rate is much closer to that found in man than the values for rats, mice and gerbils. The maximal velocity of metabolic elimination of VC at high concentrations in Rhesus monkeys is only about half that of rats when related to kg body weight. It s suggested that Rhesus monkeys mimic the quantitative aspects of VC metabolism better than rats or mice.

Animals↗