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PubMed1982

Chemical analysis and toxicity of polychlorinated biphenyls and dibenzofurans in relation to yusho.

A typical lot of Kanemi rice oil ingested by patients with yusho (PCB poisoning) and the blood, liver and adipose tissue of the patients were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) by gas chromatography and gas chromatography-mass spectrometry. The individual congeners identified were assayed for biological properties such as accumulation ability in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase and DT diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the seven PCB congeners detected in yusho patients, 2, 3, 4, 5, 3', 4'-hexa-CB seems to be the most related compound to yusho by its strong effects on induction of the liver enzymes, and on atrophy of the thymus and hypertrophy of the liver in rats. PCDF congeners identified in the patients showed severe toxicity in rats than this PCB, exhibiting stronger enzyme induction and gravimetric changes of the tissues even at very low doses of 1-10 micrograms/kg. These PCDFs, especially 2, 3, 4, 7, 8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for current symptoms of yusho.

Adipose Tissue↗
PubMed1971

Regulation of the pathway for the degradation of anthranilate in Aspergillus niger.

Studies were carried out to determine the factors governing the induction of anthranilate hydroxylase and other enzymes in the pathway for the dissimilation of anthranilate by Aspergillus niger (UBC 814). The enzyme was induced by growth in the presence of tryptophan, kynurenine, anthranilate, and, surprisingly, by 3-hydroxyanthranilate, which was not an intermediate in the conversion of anthranilate to 2,3-dihydroxybenzoate. There was an initial lag in the synthesis of anthranilate hydroxylase when induced by tryptophan, anthranilate, and 3-hydroxyanthranilate. Cycloheximide inhibited the enzyme induction. Comparative studies on anthranilate hydroxylase, 2,3-dihydroxybenzoate carboxy-lyase, and catechol 1:2-oxygenase revealed that these enzymes were not coordinately induced by either anthranilate or 3-hydroxyanthranilate. Structural requirements for the induction of anthranilate hydroxylase were determined by using various analogues of anthranilate. The activity of the constitutive catechol oxygenase was increased threefold by exposure to anthranilate, 2,3-dihydroxybenzoate, or catechol. 3-Hydroxyanthranilate did not enhance the levels of catechol oxygenase activity.

Aspergillus↗
PubMed2000

Chemoprevention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione S-transferase A5 and P1 subunits, and NAD(P)H:quinone oxidoreductase in rat liver.

Structurally diverse compounds can confer resistance to aflatoxin B1 (AFB1) hepatocarcinogenesis in the rat. Treatment with either phytochemicals [benzyl isothiocyanate, coumarin (CMRN), or indole-3-carbinol] or synthetic antioxidants and other drugs (butylated hydroxyanisole, diethyl maleate, ethoxyquin, beta-naphthoflavone, oltipraz, phenobarbital, or trans-stilbene oxide) has been found to increase hepatic aldo-keto reductase activity toward AFB1-dialdehyde and glutathione S-transferase (GST) activity toward AFB1-8,9-epoxide in both male and female rats. Under the conditions used, the natural benzopyrone CMRN was a major inducer of the AFB1 aldehyde reductase (AFAR) and the aflatoxin-conjugating class-alpha GST A5 subunit in rat liver, causing elevations of between 25- and 35-fold in hepatic levels of these proteins. Induction was not limited to AFAR and GSTA5: treatment with CMRN caused similar increases in the amount of the class-pi GST P1 subunit and NAD(P)H: quinone oxidoreductase in rat liver. Immunohistochemistry demonstrated that the overexpression of AFAR, GSTA5, GSTP1, and NAD(P)H:quinone oxidoreductase affected by CMRN is restricted to the centrilobular (periacinar) zone of the lobule, sometimes extending almost as far as the portal tract. This pattern of induction was also observed with ethoxyquin, oltipraz, and trans-stilbene oxide. By contrast, induction of these proteins by beta-naphthoflavone and diethyl maleate was predominantly periportal. Northern blotting showed that induction of these phase II drug-metabolizing enzymes by CMRN was accompanied by similar increases in the levels of their mRNAs. To assess the biological significance of enzyme induction by dietary CMRN, two intervention studies were performed in which the ability of the benzopyrone to inhibit either AFB1-initiated preneoplastic nodules (at 13 weeks) or AFB1-initiated liver tumors (at 50 weeks) was investigated. Animals pretreated with CMRN for 2 weeks prior to administration of AFB1, and with continued treatment during exposure to the carcinogen for a further 11 weeks, were protected completely from development of hepatic preneoplastic lesions by 13 weeks. In the longer-term dietary intervention, treatment with CMRN before and during exposure to AFB1 for a total of 24 weeks was found to significantly inhibit the number and size of tumors that subsequently developed by 50 weeks. These data suggest that consumption of a CMRN-containing diet provides substantial protection against the initiation of AFB1 hepatocarcinogenesis in the rat.

Aflatoxin B1↗
PubMed1983

Induction of tyrosine aminotransferase activity by concanavalin A in cultured rat hepatoma cells.

Concanavalin (Con A) induced tyrosine aminotransferase activity in cultured rat hepatoma cells (R117-21B). The highest level of the induced enzyme activity was observed at 6 to 8 hr of incubation with Con A, and the activity returned to the control level after 24 hr. This enzyme induction was dose-dependent in the range of 0.5 to 5 micrograms Con A per ml, while at higher concentrations (more than 50 micrograms/ml) the induction was very small or absent. The addition of alpha-methyl-D-mannoside abolished the effect of Con A. A 4 hr incubation of the cells with Con A and a subsequent 2 hr incubation was necessary to yield the maximal induction of tyrosine aminotransferase activity. Simultaneous incubation of the cells with Con A (5 micrograms/ml) and insulin or dexamethasone, induced tyrosine aminotransferase activity to levels higher than each activator alone, and the effect of Con A on the induction of tyrosine aminotransferase activity by dexamethasone was almost an additive. It was concluded that Con A at low concentrations mimics insulin in the induction of tyrosine aminotransferase activity in R117-21B cells, and that the effect of Con A and insulin on the induction of the enzyme is different from the effect of dexamethasone on this process.

Animals↗
PubMed1988

Inhibition of growth and induction of enzyme activities in a clonal human hepatoma cell line (Li-7A): comparison of the effects of epidermal growth factor and an anti-epidermal growth factor receptor antibody.

A cloned human hepatoma cell line (Li-7A), possessing epidermal growth factor (EGF) receptors numbering in the range of 10-20 pmol/10(6) cells, was inhibited in its growth by EGF as well as an antagonist monoclonal antibody (MoAb) to the EGF receptor. The mode of action of the two ligands of EGF receptors appeared to be different as indicated by the following results: 1) EGF induced marked alteration in cell morphology, whereas the antibody did not; 2) cellular protein accumulated in the EGF-treated cells but not in the antibody treated cells; and 3) ectoATPase activities were greatly enhanced in Li-7A cells treated with EGF and cholera toxin but were unaffected in cells treated with antibody and cholera toxin. The last result also suggests that expression of ectoATPase activities is under the regulation of both EGF and cholera toxin. Li-7A cells provide an additional valuable experimental system for the study of EGF action, as well as the interactive effects of EGF and cholera toxin. The enrichment of the ATPase activities in the EGF-cholera toxin-treated cells can be exploited for the detailed study and isolation of these enzymes and elucidation of their physiological functions.

Adenosine Triphosphatases↗
PubMed1993

Cancer chemoprotection by oltipraz: experimental and clinical considerations.

Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) is an antischistosomal drug presently under evaluation as a possible chemoprotective agent in humans. To date, oltipraz has proved effective as an inhibitor of carcinogenesis in experimental models for breast, bladder, liver, forestomach, colon, tracheal, lung, and skin cancer. Studies on the mechanisms of action of oltipraz indicate that it affects the metabolism and disposition of chemical carcinogens, principally through the induction of electrophile detoxication enzymes. While this feature is common to many different classes of both natural and synthetic experimental chemoprotectors (i.e., phenolic antioxidants, isothiocyanates, flavonoids, indoles, cinnamates, coumarins, terpenes, and others), oltipraz may offer the earliest and easiest prospect for examining the role of enzyme induction as a protective strategy in humans. Unlike the situation with many of the anutrients, substantial preclinical research has already been conducted with oltipraz to establish its safety and efficacy in animals. Hopefully, Phase I investigations will demonstrate a high tolerance for oltipraz in the chemoprotective dose range of the drug. A major concern for the success of any trial is selecting participants who are likely to adhere to the intervention as well as to all aspects of the protocol. Factors influencing participation and adherence in a trial include the design of the trial, the nature of the disease under study as well as the nature of the intervention, in particular the toxicities of the intervention (J. A. Tangrea, M. E. Adrianza, and W. E. Helsel, Cancer Epi Biomarkers Prev 1992; 1:325-330). Chemoprotection trials with oltipraz have an excellent prospect for success. Individuals with known carcinogenic exposures are likely to be interested in participation in trials designed to reduce the risks of the exposures. Moreover, the availability of intermediate markers reflecting the modulation of the biologically effective dose of environmental carcinogens as study end points will enable efficient trials to be designed.

Animals↗
PubMed1979

[Tumor prevention by vitamin A: in vitro studies with human cultured fibroblasts (author's transl)].

Following the well established prevention of chemical carcinogenesis by vitamin A in several species of laboratory animals, we performed in vitro studies with human diploid fibroblasts in culture. Vitamin A-palmitate, alltransretinoic acid and the analogue compound Ro 10-9359 were found to reduce the formation of active intermediates following the administration of G3H Benzo(a)pyrene to the cells. This effect which lead to a considerable decrease of alkylated DNA is not based on a direct inhibition of Benzpyrene metabolizing enzymes by the retinoids but by a preferential inhibition of the de novo synthesis of these enzymes. This caused the well known substrate mediated enzyme induction of benzpyrene metabolizing enzymes to cease. From our data we conclude that the mechanism of the cancer protective effect of vitamin A with respect to certain carcinogens is based on an inhibited activation of procarcinogens. This effect can also be expected in human tissues.

Benzopyrenes↗
PubMed1980

Dose-dependence and related studies on the pharmacokinetics of misonidazole and desmethylmisonidazole in mice.

An understanding of lipophilicity and pharmacokinetics is important in developing alternative radiosensitizers to misonidazole (MIS). Analogues more hydrophilic that MIS, including its O-demethylated metabolite DEMIS (Ro 05-9963), appear promising candidates. In vivo testing is usually carried out in mice, and the present paper reports dose-dependence and related studies on the comparative kinetics of MIS and DEMIS in this species. The data are consistent with a model in which MIS is eliminated mainly by metabolism, including demethylation to DEMIS, and saturable (non-linear) kinetics are exhibited. Apparent t 1/2 increased with dose. But DEMIS is eliminated mainly by renal clearance exhibiting first-order (linear) kinetics. PHenobarbitone reduced the t 1/2 and toxicity of MIS but not of DEMIS. SKF 525A increased the t 1/2 of MIS. The following were not responsible for the non-linear kinetics of MIS: short-term enzyme induction by MIS; potent enzyme inhibition by the product DEMIS; decrease in body temperature by MIS; injection volume; and protein binding. For both MIS and DEMIS peak blood concentrations were about 2-fold lower for IP than IV injection. The IP bioavailability of DEMIS (1.07 mmol/kg) was 100%, but that of MIS (1 mmol/kg) was 80%, suggesting some first-pass metabolism. Both MIS and DEMIS were absorbed more slowly and gave lower peak blood concentrations after IP injection in a large (40 ml/kg) as against a small (10 ml/kg) volume. Peak concentrations were lower for equimolar IP DEMIS, but this was less marked at lower doses. With both MIS and DEMIS, tumour/blood and brain/blood ratios were slightly increased at higher doses. Some kinetic differences were also observed between male and female mice. The above findings, particularly the major differences in elimination kinetics between MIS and DEMIS, should be considered in in vivo experiments with nitroimidazoles.

Animals↗
PubMed1987

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Adult↗
PubMed1993

Tryptamine: a metabolite of tryptophan implicated in various neuropsychiatric disorders.

Although early interest in the biomedical relevance of tryptamine has waned in recent years, it is clear from the above discussion that the study of tryptamine is worthy of serious consideration as a factor in neuropsychiatric disorders. The study of [3H]-tryptamine binding sites indicates an adaptive responsiveness characteristic of functional receptors. The question raised by Jones (1982d) on whether tryptamine is acting centrally as a neurotransmitter or a neuromodulator still remains mostly unanswered, although the evidence cited within this review strongly suggests a modulatory role for this neuroactive amine (see also Juorio and Paterson, 1990). The synthesis and degradative pathways of tryptamine, as well as the intricate neurochemical and behavioral consequences of altering these pathways, are now more fully understood. It is not yet clear what the role of tryptamine is under normal physiological [homeostatic] conditions, however, its role during pathological conditions such as mental and physical stress, hepatic dysfunction and other disorders of metabolism (i.e. electrolyte imbalance, increased precursor availability, enzyme induction or alterations in enzyme co-factor availability) may be quite subtle, perhaps accounting for various sequelae hitherto considered idiopathic. The evidence for a primary role for tryptamine in the etiology of mental or neurological diseases is still relatively poor, although the observations that endogenous concentrations of tryptamine are particularly susceptible to pharmacological as well as physiological manipulations serve to reinforce the proposition that this indoleamine is not simply a metabolic accident but rather a neuroactive compound in its own right. Finally, one might wonder what proportion of the data attributed to modifications of 5-HT metabolism might, in fact, involve unrecognized changes in the concentrations of other neuroactive metabolites of tryptophan such as tryptamine.

Animals↗