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Biomedical subjects

M Metzler

Publications and source records attributed to M Metzler.

At least 163 records · Page 9Linked to original sources
PubMed1978

Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs.

The diethylstilbestrol (DES) metabolite (beta-dienestrol), which had been identified in mouse, rat, monkey, and human urine, and two proposed metabolic intermediates (diethylstilbestrol alpha,alpha'-epoxide and alpha,alpha'-dihydroxy DES) were synthesized and their estrogenic activities determined. In addition, three DES analogs, alpha-dienestrol, DES-dihydroxy diethyl phenanthrene (DES-phenanthrene), and 1-(alpha-ethyl, 4alpha-hydroxyphenyl)indanyl-5-ol (indanyl-DES), were studied. Estrogenic activities of the compounds in vivo were determined by the immature mouse uterine weight bioassay; in vitro, their estradiol receptor binding activity (competitive equilibrium binding, sucrose gradient analysis, and association rate inhibition assays) was determined. Results of the mouse uterine weight bioassay gave the following order of estrogenicity: DES > alpha-dienestrol >/= DES-epoxide > indanyl-DES > dihydroxy DES > beta-dienestrol > DES-phenanthrene. Results of competitive equilibrium binding analyses of these compounds with estradiol-17beta for the mouse uterine cytosol receptor followed the same order seen for the bioassay, except for indanyl-DES. DES, indanyl-DES, and alpha-dienestrol had the greatest affinities (K(a) values approximately 0.5-19.1 x 10(10) M(-1)), while DES-phenanthrene had the lowest (K(a) = 3.5 x 10(7) M(-1) +/- 1.2). Sucrose gradient analysis of the above competition preparations illustrated the displacement of [(3)H]estradiol from the receptor peak. This displacement was receptor specific and concentration dependent and correlated with the equilibrium binding concentrations. In addition, the most hormonally active substances demonstrated the greatest rate inhibition in the estradiol cytosol receptor association rate reaction (V(0)). The rank order of estrogenicity of the compounds determined in this study should be useful in evaluating alternative metabolic pathways of DES as well as distinguishing biologically active metabolites from relatively inactive ones.

Binding, Competitive↗
PubMed1977

Metabolic activation of diethylstilbestrol and aminostilbene-derivatives.

Diethylstilbestrol and trans-4-dimethylaminostilbene are metabolically activated and several of their metabolites are able to react with cellular macromolecules. Some of the problems are discussed which are encountered in linking a particular metabolite with the mutagenic and carcinogenic properties of these compounds.

Animals↗
PubMed1977

Carcinogenicity of trichloroethylene: fact or artifact?

Technical trichloroethylene has been found carcinogenic in mice after high daily doses per os. A GC-MS analysis of this technical sample revealed the presence of considerable amounts of epichlorohydrin and 1.2-epoxibutane as stabilizers. These epoxides are highly mutagenic in the Ames test and are, most probably, responsible for the carcinogenic effect found in mice. The question whether trichloroethylene is carcinogenic or not remains open.

Carcinogens↗
PubMed1977

Biotransformation of diethylstilbestrol in the rhesus monkey and the chimpanzee.

Diethylstilbestrol (DES) is considered a teratogen and a transplacental carcinogen in humans. In order to compare its biotransformation in nonhuman primates to that in humans, a metabolic study was carried out in rhesus monkeys and chimpanzees. After an oral dose of 1 mg/kg [14C]DES, approximately 59% of the ingested radioactivity was found in the urine and 28% in the feces of two female rhesus monkeys after 4 days, while in male rhesus monkeys urinary radioactivity accounted for 43% and fecal radioactivity for 35%. In chimpanzees, 63% of a 0.5 mg/kg dose was excreted with the urine in a female and 47% in a male animal. In both species, urinary radioactivity was predominantly (greater than 70%) associated with glucuronides. Besides DES, three metabolites were found in the urinary glucuronide fraction of rhesus monkeys and chimpanzees by radio gas chromatography and were identified as dienestrol and omega-hydroxy derivatives of DES and dienestrol. Fecal radioactivity in rhesus monkeys was shown to consist exclusively of DES. Glucuronidation of DES appears to occur in neonatal and fetal rhesus monkeys.

Animals↗
PubMed1977

Epoxidation of the stilbene double bond, a major pathway in aminostilbene metabolism.

1. The vicinal diol 1-(4-acetylamino)-phenyl-2-phenyl-1,2-ethanediol is shown to be a major metabolite of cis- and trans-4-dimethylaminostilbene in the rat. 2. The threo-diastereomeric diols were identified in urine with both the cis- and trans-aminostilbene. This is consistent with enzymic trans-opening of an epoxide intermediate only for the cis-stilbene. For the hydrolysis of the trans-stilbene epoxide alternative mechanisms are discussed. 3. A mercapturic acid isolated from urine is identical with the reaction product of 4-acetylaminostilbene epoxide and N-acetylcysteine. This provides additional evidence for an epoxide intermediate. 4. Oxidation of the intercyclic linkage occurs also in 4-dimethylaminobibenzyl, leading to 1-phenyl-2-(4-acetylamino)-phenyl-1-ethanol as a major urinary metabolite. 5. The syntheses of several reference compounds, including the epoxides and dihydrodiols of cis- and trans-4-acetylaminostilbene are described.

Animals↗
PubMed1976

Metabolic epoxidation of trans-4-acetylaminostilbene: a protective mechanism against its activation to a mutagen.

Trans-4-acetylaminostilbene is activated by liver preparations to mutagens for Salmonella typhimurium. Since this compound is metabolized to the trans-alpha,beta-epoxide and since many epoxides are ultimate mutagens, this epoxide was tested for direct mutagenicity. It was, however, found to be non-mutagenic, and, in contrast to the parent compound, the epoxide was no longer activated by liver preparations to mutagens. The same was found for the beta-ketone and for the threo-alpha,beta-dihydrodiol, which are formed metabolically from trans-4-acetylaminostilbene and from its alpha,beta-epoxide. 4-Acetylaminobibenzyl showed a very weak mutagenic activity in the presence of the liver preparation. Thus, it is important to realize that where epoxides are formed from compounds which are known to be metabolized to mutagens, they are not necessarily responsible for the mutagenicity. Epoxidation may even prevent the possibility of bioactivation to mutagens.

Animals↗
PubMed1976

Metabolic activation of carcinogenic diethylstilbestrol in rodents and humans.

In vivo biotransformation of diethylstilbestrol (DES) was studied by radio-GLC and GLC-mass spectrometry using both radioactively and deuterium-labeled DES. Among the urinary and biliary metabolites identified in intact Wistar rat and Syrian golden hamsters are dienestrol and hydroxy and methoxy derivatives of dienestrol and DES. The identification of 4'-hydroxypropiophenone as a urinary metabolite of DES in the rat is consistent with the hypothesis that dienestrol is formed via an epoxide-diol pathway. Some of the metabolites imply electrophilic reactivity according to their chemical structure and may represent proximate carcinogens of DES. In humans, dienestrol and hydroxy dienestrol constitute the major urinary DES metabolites in men and were also identified in the urine of a woman. Considerable species differences in DES metabolism between humans and rats were found with regard to the route of excretion and the pattern of urinary metabolites.

Adult↗
PubMedDate not supplied

Effect of 7,8-benzoflavone pretreatment on diethylstilbestrol metabolism, drug-metabolising enzymes and the aromatic hydrocarbon (Ah) receptor in male hamster liver.

Pretreatment of male Syrian golden hamsters with 7,8-benzoflavone (7,8-BF) leads to a marked increase of cytochrome P450 and cytochrome b5 levels in the liver, whereas phenobarbital (PB) and 3-methylcholanthrene (MC) induce cytochrome P450 but not cytochrome b5 7,8-BF pretreatment has only minor effects on the activities of aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase, but 7-ethoxyresorufin-O-deethylase is increased 3-fold. In contrast to PB, pretreatment with 7,8-BF or MC reduces the oxidative metabolism of diethylstilbestrol (DES) by hepatic microsomes in vitro. The cytosolic level of the aromatic hydrocarbon (Ah) receptor in hamster liver is decreased by 7,8-BF and slightly enhanced by MC pretreatment. PB increases the receptor level 1.5-fold. The affinity of 7,8-BF to the Ah receptor in vitro is of the same order of magnitude as that of the known ligands 5,6-benzoflavone and 2,3,7,8-tetrachlorodibenzofurane. PB and DES show no binding to the receptor protein.

Animals↗