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This thesis focuses on some analytical and pharmacological aspects of enantiomers. Enantiomers always exist as a pair of non-identical mirror-images that resemble each other as a left and a rigbt hand. The configuration around the central (carbon) atom is opposite. This remarkable relationship can result in large differences in biological activity befween the enantiomers (Chapter I.1). ... Zie: Samenvatting

2-Chlorobenzaldehyde might be produced when a moist skin is exposed to the riot control agent CS. CS-hydrolysis to 2-chlorobenzaldehyde and malononitrile occurs both in vitro and in vivo. No quantitative data have thus far been reported with respect to the percutaneous absorption and the cutaneous biotransformation of 2-chlorobenzaldehyde. Percutaneous absorption, biotransformation and elimination of 14-C-labelled 2-chlorobenzaldehyde was investigated in the rat. Following IV (25 microliters/kg) and IP (37.5 microliters/kg) 14C-2-chlorobenzaldehyde administration to rats, the plasma radioactivity declined rapidly over a 24 h period with similar plasma radioactivity-time profiles. Following cutaneous administration (75 microliters/kg) in a closed glass-cup on the skin a slow skin penetration occurred as indicated by plasma radioactivity levels. A slow increase in plasma radioactivity was followed by a slow decline of radioactivity in plasma over a 3-day period. Most of the radioactivity was found in the urine with low levels in faeces and exhaled air. The cutaneously administered radioactivity was also partly recovered from the glass-cup. For the qualitative and quantitative determination of metabolites in urine, a thin layer chromatography-radioautography method was used. The metabolic patterns of urinary excreted metabolites following cutaneous application and systemic administration of 14C-2-chlorobenzaldehyde to rats were very similar. No parent compound was recovered from the rat urine. 2-Chlorohippuric acid was the principal urinary metabolite. Quantitatively, the urinary excretion of 14C-2-chlorobenzyl alcohol following cutaneous application differed substantially from that after the systemic administration. There was no evidence of storage in the skin or skin toxicity of 2-chlorobenzaldehyde following cutaneous application.

Adult male Wistar rats administered i.p. with 2-chlorobenzylidene malononitrile (CS) excreted one mercapturic acid in urine. The amount of mercapturic acid determined gaschromatographically was about 4% of the dose (0.07 mmol/kg, n = 12). The structure of the mercapturic acid methylester was identified by t.l.c. and confirmed by synthesis and mass-spectrography. The acid appeared to be 2-chlorobenzylmercapturic acid [N-acetyl-S-(2-chlorobenzyl)-L-cysteine]. CS and some of its metabolites were also tested in the Ames Salmonella/microsome assay. Both mutagenic and toxic effects were measured with strain TA 100 as the indicator organism. No mutagenic effects were found with any of the tested substances. At dosages of CS, higher than 1,000 micrograms/plate a bacteriotoxicity was revealed.

Oral contraceptive steroids increased the residence time of caffeine in 9 young women by a factor of 2. The effect was already manifested during the first cycle 2 weeks after starting oral contraceptive steroids (OCS) and was slightly increased in the second cycle, after 6 weeks on OCS. Toxic effects attributed to oral contraceptive steroids may in part be indirect and due to prolonged retention of absorbed toxic agents to which women are exposed.Oral contraceptives (OCs) increased the residence time of caffeine in 9 young women by a factor of 2. The effect was already manifested during the 1st cycle 2 weeks after beginning OCs and was slightly increased in the 2nd cycle, after 6 weeks on OCs. Toxic effects attributed to OCs may in part be indirect and due to prolonged retention of absorbed toxic agents to which women are exposed.

After administration of substituted (CH3, OH, OCH3, F, CL, Br, NO2) benzaldehyde or benzyl alcohols in the rat an enhanced urinary thioether excretion was found in some cases. With p-substituted benzaldehyde only occasionally a slight increase could be shown, but with o-substituted aldehydes and alcohols thioether excretions amounted up to 13% of the dose. Mercapturic acids were isolated and identified by synthesis, mass-, and n.m.r.-spectrometry as the arylmethyl thioethers of N-acetylcysteine. Steric hindrance by o-substituents must be the main cause of a relative decrease in oxidation to the carboxylic acid and an increase of the importance of both the reduction of the aldehydes and the reaction of the alcohols, presumably to sulphuric acid esters, as intermediates for the alkylation of glutathione. Consequently, previous administration of pyrazole, an inhibitor of alcohol dehydrogenase, caused an even larger thioether excretion after injection of o-chlorobenzyl alcohol.

Male adult Wistar rats dosed i.p. with o-substituted benzaldehydes (o-F, o-Cl, and o-Br = V, VI, and VII) excreted mercapturic acids in urine. These acids were identified as N-acetyl-S-(ortho-substituted benzyl)cysteines (I, II, III). The total mercapturic acid excretion as % dose (2.0 mmol/kg, n = 4) was 1.2 +/- 0.4, 6.8 +/- 0.9, and 10.4 +/- 2.0 for V, VI, and VII. p-Cl-benzaldehyde administered in the same dose showed a non-significant urinary thioether excretion. The aim of the investigation was to prove in vivo a postulated metabolic pathway of substituted benzaldehydes via sulphate esters to mercapturic acids. After a single administration of the sodium salts of o- and p-Cl-benzylsulfuric acid a significant increase in mercapturic acid excretion of 21.2 +/- 1.8% and 14.5 +/- 1.2% of dose (2.0 mmol/kg, n = 4) was found. By pretreatment with pyrazole the mercapturic acid excretion increased after administration of o-Cl-benzyl alcohol (IX) whereas a significant decrease was found after administration of o-Cl-benzaldehyde (VI). After simultaneous administration of ethanol with IX and VI an increase in mercapturic acid excretion was observed. After previous administration of pentachlorophenol a significant decrease in urinary mercapturic acid excretion for IX and VI was found. These findings are in accordance with a metabolic pathway of substituted benzaldehydes via benzyl alcohols, subsequently sulphate esters to the corresponding benzylmercapturic acids.

This paper describes the ability of racemic, and enantiomerically pure cis- and trans-methyl epoxycinnamates (methyl 3-phenyl-2,3-epoxy-propanoates) to undergo glutathione conjugation and subsequent excretion as mercapturic acid and on the mutagenicities of these epoxy esters in the Ames assay. In incubation mixtures containing rat liver cytosol (9,000 g), the decrease of glutathione due to the epoxy esters occurred enzymatically. The highest glutathione depletion was found for the cis-epoxy cinnamic esters. Adult male rats administered a single i.p. dose of racemic trans- and cis-epoxy cinnamates (0.7 mmol/kg, n = 4) excreted thioethers in urine. Higher urinary thioether excretion was found after the cis-epoxy ester dosing. The structures of the thioether metabolites isolated from the urinary extracts were identified by TLC and confirmed by synthesis and mass spectrometry (FAB+). The thioethers appeared to be hydroxy mercapturic acids. The N-alkylating potential of the racemic epoxy esters was determined using 4-(p-nitrobenzyl)pyridine (= NBP). The trans-epoxy ester appeared to react much better with NBP than the cis-compound. Mutagenic effects of racemic trans-epoxy cinnamate as well as the enantiomerically pure trans-epoxy cinnamates were observed in the Ames test with S. typhimurium strains TA1535, TA1537, TA1538 and TA100 without metabolic activation. No mutagenic responses were detected using any of the epoxy cinnamates with S9 activation. By comparing the mutagenicity and the enzymatically catalyzed glutathione conjugation it follows that the activity of the respective enantiomeric methyl cinnamates goes in the opposite order. Glutathione conjugation plays a protective role in the detoxication in living organism of the potentially toxic methyl epoxy cinnamates.

Zusammenfassung Stoffwechsel und Speicherung von Radio-Caesium im Gewebe von Mastkalbern wahrend der Mast Es wurden der Stoffwechsel von Radio-Caesium bei Mastkalbern untersucht. Drei Versuchsgruppen wurde mit Milchaustauschern mit unterschiedlichen Gehalten an Radio-Caesium gefuttert. Die verabreichte Dosis in den jeweiligen Gruppen betrug in Gruppe I (Kontrolle) 0,24 Bq/kg. Tag, in Gruppe II 3,5 Bq/kg. Tag und in Gruppe III 8,3 Bq. Tag. Das Caesium wurde hauptsachlich mit dem Harn ausgeschieden (65% der taglich verabreichten Dosis). Mit dem Kot wurden zusatzlich 5 % ausgeschieden. Nach einer Versuchsdauer von 154 Tagen lag die Gesamtausscheidung der Nuklide noch immer unter 100% der taglich verabreichten Dosis. Diese Beobachtung last vermuten, das zu diesem Zeitpunkt noch eine Speicherung von Caesium stattfand. Die Hohe der Konzentration an Caesium im Muskelgewebe war linear mit der verabreichten Dosis korreliert und betrug nach 150 Tagen 6, 130 und 277 Bq/kg in den Gruppen I, II und III. Die Messung von Radio-Caesium im Muskelgewebe nach 66, 94, 119 und 150 Tagen, zeigten, das nach 66 Tagen nur noch eine geringe Zunahme der Caesium-Konzentration auftrat.

After administration of substituted (CH3, OH, OCH3, F, CL, Br, NO2) benzaldehydes or benzyl alcohols in the rat an enhanced urinary thioether excretion was found in some cases.