Biomedical subjects
Publications and source records attributed to M Metzler.
Leisure time all-terrain vehicle (ATV) use and injuries are increasing. The authors characterize the riding habits and injury patterns of patients hospitalized for ATV-related trauma and offer suggestions for decreasing ATV injuries.
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The metabolism of the animal growth promotants diethylstilbestrol, zeranol and 17 beta-trenbolone and of a few anabolizing steroids used in humans is briefly reviewed. The possible role of reactive metabolic intermediates in the toxicity of some anabolic agents is discussed. Analytical implications of the metabolism of anabolizing agents are described and examples of the analysis of metabolites by means of recently developed techniques are given. It is proposed to utilize the covalent binding of reactive metabolites of anabolic compounds to blood proteins such as haemoglobin and serum albumin for retrospective doping analysis.
Two male English Setters were noticed to be breathing rapidly, hyperexcitable, and atactic after roaming a rural area for 2 hours. Both dogs' cost were stained with yellow liquid. One dog died while en route to the veterinarian. Treatment was begun for the surviving dog for what was initially diagnosed to be organophosphorus or carbamate insecticide toxicosis. Before the diagnosis could be confirmed, the second dog died. The yellow liquid on the dogs' skin was identified as dinoseb in high concentrations. Dinoseb is an acutely toxic, substituted dinitrophenolic herbicide believed to act as an uncoupler of electron transport from oxidative phosphorylation.
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A full-length cDNA encoding the murine interferon gamma (IFN-gamma) receptor was isolated from a lambda gt11 library using a human IFN-gamma receptor cDNA probe. The deduced amino acid sequence of the murine IFN-gamma receptor shows approximately 53% homology to its human counterpart but no homology to other known proteins. Murine IFN-gamma receptor cDNA was expressed in human HEp-2 cells, which do not bind murine IFN-gamma and are insensitive to its action. Transfectants displayed the same binding properties as mouse cells. The biological responsiveness of such transfectants to various biological effects of both human and murine IFN-gamma was investigated, including modulation of major histocompatibility complex class I and class II antigen expression, inhibition of cell growth, and antiviral activity. Like parental HEp-2 cells, these transfectants responded only to human, but not to murine, IFN-gamma. Inversely, mouse L929 cells transfected with human IFN-gamma receptor cDNA were insensitive to human IFN-gamma. These results confirm and extend previous findings, suggesting that species-specific cofactors are needed for IFN-gamma-mediated signal transduction.
The prostaglandin H synthase (PHS)-catalyzed metabolism of indenestrol A (IA), indenestrol B (IB) and indanestrol (I) and the effects of these compounds on PHS were studied in incubations with ram seminal vesicle microsomes (RSVM) by means of arachidonic acid (20:4)-dependent oxygen consumption and by HPLC analysis of parent compound conversion as well as UV spectroscopy. IA and I were metabolized by PHS via co-oxidation. By analogy with diethylstilbestrol (DES) they stimulated PHS cyclo-oxygenase dose-dependently and became inhibitory at higher concentrations. Cyclo-oxygenase activity determined at 20:4 concentrations ranging from 10 to 70 microM revealed an antioxidant-type of inhibition for IA with IC50 values ranging from 30 to 150 microM. IB, on the other hand, displayed an indomethacin-like type of PHS inhibition with an IC50 value of 20 microM not dependent upon 20:4 concentration which was consistent with the observation that IB inhibited the co-oxidation of DES when initiated with 20:4 but not with hydrogen peroxide. Recovery of IB was incomplete in extracts from incubations with native PHS, but the reaction was neither 20:4 dependent nor inhibited by indomethacin or catalase; it was partially inhibited by eicosatetraynoic acid (ETYA) or by butylhydroxyanisol (BHA). This may indicate affinity of IB for the enzyme protein and conversion of IB other than by a co-oxidation mechanism. UV spectroscopy revealed the formation of a p-quinoid intermediate in incubations with IA, but not with IB or I. The IA-quinone was synthesized and reacted with nucleophiles such as water, methanol, ethanol and mercaptoethanol to adducts which were further characterized by gas chromatography/mass spectrometry. Our data indicate that indanyl derivatives of DES interact differently with PHS and thus could provide a useful tool for future studies on the mechanism of action of tumorigenic stilbene estrogens as well as on the elucidation of the role of PHS-mediated metabolism in their toxic action.
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Incidental discovery of a mass during laparoscopic surgery resulted in exploratory laparotomy for a young woman. The mass' uncharacteristic appearance belied its true identity as displaced splenic tissue. The authors suggest ways to identify splenosis without resorting to further surgery.
Liver tumors are induced in male Syrian golden hamsters by the combined treatment with diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF), but not with either substance alone. With the aim of clarifying whether metabolic activation of DES is involved in the mechanism of tumorigenesis in this animal model, we have studied the effect of pretreatment with 7,8-BF alone, DES alone, and 7,8-BF plus DES for 2, 8, 20 and 32 weeks on the hepatic in vivo metabolism of DES, using biliary metabolites collected from bile-duct cannulated male hamsters as probe. Formation of glucuronides and sulfates was not affected by treatment with 7,8-BF nor 7,8-BF plus DES. In contrast, animals pretreated with DES alone had a decreased amount of glucuronides and an increased proportion of unconjugated material in the bile. Oxidative metabolism of DES was not significantly altered in hamsters treated with 7,8-BF for up to 20 weeks, whereas pretreatment with DES alone and with 7,8-BF plus DES caused an enhancement of oxidative DES metabolism in vivo, leading mostly to highly polar, as yet unidentified products. From a consideration of various cytochrome P-450-associated enzyme activities, it is concluded that the observed effect on biliary DES metabolites is most likely to be due to an estrogen-induced intrahepatic cholestasis. Taken together, the data do not support a role for the metabolic activation of DES in this tumor model. Alternative mechanisms are proposed.
The influence of alpha-naphthoflavone (ANF) on the metabolism and binding of radiolabeled ethinylestradiol (EE2) has been examined both in vitro and in vivo in hamster liver microsomes. [14C]EE2 was metabolized extensively to seven major oxidative metabolites, 7 alpha-hydroxyEE2, 4-hydroxyEE2, 2-hydroxyEE2, D-homoestrone, monohydroxyEE2, and two dihydroxyEE2 metabolites identified as catechols with the additional hydroxy group on ring B or C, and a nonpolar fraction. The main EE2 metabolite found was 2-hydroxyEE2, and it represented 47% of the total metabolites formed. The total amount of EE2 catechol metabolites formed in untreated hamster liver microsomes was 65.5%. When ANF was added in vitro to these hepatic microsomes, there was a 27-45% decline in 2-hydroxyEE2 formation, a 98% reduction in dihydroxyEE2 (catechol-2), and a 56-66% reduction in the nonpolar fraction. The marked inhibition of EE2 metabolism by the in vitro addition of ANF is reflected by a corresponding decrease in the irreversible binding of radioactive hormone to hamster liver microsomal proteins. In contrast, a biphasic response of ANF on EE2 metabolism was observed after in vivo administration for 2.0 and 4.0 months. After 2.0 months of ANF treatment, there was a modest decline in all [14C]EE2 metabolites, except 2-hydroxyEE2 and dihydroxyEE2 (catechol 1). After 4.0 months of ANF treatment, the reduction in EE2 metabolism was even lower than after 2.0 months of treatment. Most interestingly, there was a 1.5-fold increase in 2-hydroxyEE2 after 4.0 months of ANF treatment, representing nearly 69% of the total EE2 metabolites formed. These results are consistent with an increase in irreversible binding of [14C]EE2 metabolites to hamster liver microsomal proteins after 4.0 months of ANF treatment. The relative 1.3-fold and the absolute 1.5-fold increases in 2-hydroxyEE2 after 2.0 and 4.0 months of ANF treatment in vivo, respectively, suggest that the elevation in this reactive EE2 metabolite precursor may contribute importantly to hepatotumorigenesis in the hamster following prolonged EE2 plus ANF treatment.
The synthetic androgen 17 beta-trenbolone (beta-TBOH), used as a growth promotant in cattle, and its metabolite 17 alpha-trenbolone (alpha-TBOH) were tested for genetic toxicity in Syrian hamster embryo (SHE) cells and in mouse C3H10T1/2 embryo fibroblasts by measuring the induction of micronucleus formation and neoplastic cell transformation. Both beta-TBOH and alpha-TBOH, but not testosterone nor its hormonally active metabolite, 5 alpha-dihydrotestosterone, caused a dose-related induction of micronuclei in SHE cells. In C3H10T1/2 cells, neither beta-TBOH nor alpha-TBOH gave rise to micronucleus induction. Furthermore, both beta-TBOH and alpha-TBOH, but not testosterone, were found to transform SHE cells but not C3H10T1/2 cells morphologically. The beta-TBOH-transformed SHE cells proved to be neoplastic in thymus-aplastic nude mice. These data show that beta-TBOH is able to cause changes at the chromosomal level and neoplastic transformation independent of its hormonal activity in one mammalian cell system but not in another one. The implications of these data for the risk evaluation of beta-TBOH are discussed.
The activities of 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-deethylase (PROD), 7-ethoxycoumarin-O-deethylase (ECOD) and aromatic hydrocarbon hydroxylase (AHH) were measured in hepatic microsomes from male and female Wistar rats and Syrian golden hamsters in order to probe the basal activity and the inducibility by phenobarbital (PB) and 3-methylcholanthrene (MC) of different P-450 isoenzymes. The basal activities of EROD and ECOD, but not PROD and AHH, were higher in male hamsters than in male rats. No sex-related difference in enzyme activities was observed with hamsters, whereas male rats had a higher ECOD and AHH activity than female rats. Induction by PB led to a 450-fold and 250-fold increase in PROD activity in male and female rat liver microsomes, respectively, while MC had a more pronounced inductive effect on EROD activity in this species. In hamsters, EROD activity was induced by MC but not by PB. Unexpectedly PROD activity in male and female hamster liver microsomes was only moderately induced by PB, the extent being lower than on induction by MC. Therefore, the activity of PROD, which is useful as a specific enzymatic assay for P-450 IIB in the rat liver, cannot be used to probe PB-like inducers in the hamster liver.
Combined treatment of male Syrian golden hamsters with the synthetic estrogen diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF) gives rise to a high incidence of hepatocellular carcinomas, whereas no such tumors are formed with DES alone nor with 7,8-BF alone. To determine whether alterations in DES metabolism may account for the observed hepatocarcinogenicity, we have studied the effect of pretreatment with 7,8-BF alone, DES alone and 7,8-BF plus DES on the levels of hepatic P-450 and cytochrome b5, on the activities of various P-450 isoenzymes and on microsomal DES metabolism. Hepatic P-450 content was significantly increased after pretreatment with 7,8-BF and decreased after DES, while combined pretreatment led to levels similar to those in untreated control animals. Hepatic cytochrome b5 was also elevated in 7,8-BF-treated hamsters; DES pretreatment had no effect, and combined pretreatment led to a slight increase. Four different substrates were used to probe P-450 isoenzyme activity. Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin-O-deethylase (ECOD), 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) were all elevated after 7,8-BF-pretreatment, while DES led to a decrease in these activities with the exception of AHH, where a transient increase which was observed after 8 and 20 weeks of pretreatment was back to control levels after 32 weeks. Combined pretreatment with 7,8-BF and DES led to an intermediate response (slight increase) with AHH, EROD and PROD, but not with ECOD, where a full induction comparable with that observed after 7,8-BF alone was elicited. In spite of the modulation of enzyme levels and activities observed after the various pretreatments, the metabolism of DES in microsomes from pretreated animals was virtually identical with that from controls. Therefore it is concluded that modulation of hepatic DES metabolism is not the reason for the observed hepatotumorigenicity; instead, it is speculated that 7,8-BF is the carcinogenic agent in this tumor model, and DES may act as a promotor.
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1. Pretreatment of male Syrian golden hamsters with 7,8-benzoflavone (7,8-BF, 0.4% in the diet) for 4 and 20 weeks resulted in a significant increase in the amount of cytochrome P-450 and cytochrome b5 in hepatic microsomes. The activities of microsomal 7-ethoxycoumarin-O-deethylase (ECOD) and 7-ethoxyresorufin-O-deethylase (EROD) increased by a factor of 2 and 5, respectively, whereas aryl hydrocarbon hydroxylase (AHH) activity was only marginally enhanced. 2. Because the relative increase in cytochrome b5 exceeded that of cytochrome P-450, the ratio of P-450 to b5 decreased from 2.2 in controls to 1.6 in 7,8-BF-treated animals. 3. Hepatic microsomes from untreated and 7,8-BF-pretreated hamsters metabolize E-diethylstilboestrol (E-DES) to its stereoisomer Z-DES and to several oxidative metabolites, of which 3-hydroxy-DES and Z,Z-dienestrol were unambiguously identified by g.l.c.-mass spectrometry. 4. Pretreatment with 7,8-BF led to a marked decrease in the formation of all oxidative DES metabolites but not in the isomerization to Z-DES. The possible implication of these data for the mechanism of liver tumour formation by the combined treatment of hamsters with 7,8-BF and DES is discussed.