Studies on 5-hydroxytryptophol and the metabolic interaction between serotonin and ethanol
Sammanfattning: The biogenic amine serotonin (5-hydroxytryptamine, 5HT) is most abundant within the gastrointestinal tract (GIT), in blood platelets, and in the central nervous system. The 5HT system is involved in many physiological and behavioural processes in the body. 5HT is metabolised by monoamine oxidase to 5-hydroxyindole-3-acetaldehyde (5HIAL), which is either oxidised to the major metabolite 5-hydroxyindole-3 -acetic acid (5HIAA) by aldehyde dehydrogenase or reduced to the minor metabolite 5-hydroxytryptophol (5HTOL) by alcohol dehydrogenase (ADH). Acute ethanol intake alters the metabolic conversion of 5HIAL from the oxidative toward the reductive pathway resulting in an elevated 5HTOL/5H1AA ratio. After ethanol has been eliminated from the body, the urinary 5HTOL/5HIAA ratio remains increased for several hours. Based on this time-lag, an increased urinary 5HTOL/5HIAA ratio is used clinically as a biochemical marker of recent alcohol intake. This thesis focuses on the metabolism of 5HT, and the location and underlying mechanisms of the metabolic interaction with ethanol. In rat, the highest 5HT turnover was found in kidney, lung and colon in vivo and a significant metabolic interaction between 5HT and ethanol was observed in liver. However, in rat tissue homogenates this metabolic interaction via the ADH pathway was demonstrated to take place in several tissues besides the liver, e.g. in kidney, lung and within the GIT, indicating capacity to metabolise both ethanol and 51-HAL via ADH within those tissues in vivo. The time delay observed in urinary 5HTOL excretion was proposed to be due to the extra metabolic step necessary to conjugate this rather lipophilic substance. The reversible reduction of 5HIAL to 5HTOL mediated via the ADH pathway was investigated for different classes of ADH in vitro. Class I Y272 ADH was shown to efficiently catalyse 5HIAL reduction in the presence of NADH, implying that the increased 5HTOL/5HIAA ratio seen after ethanol intake may be an effect of the increased NADH/NAD+ ratio on class I ADH. Furthermore, the rat was found to have a much higher basal urinary 5HTOL/5HIAA ratio than man, which was concluded to be due to a higher relative formation of 5HTOL. This results in a less pronounced shift in the 5HT metabolism due to ethanol oxidation in the rat compared with man. An increased urinary 5HTOL/5HIAA ratio is used clinically as a marker of recent alcohol intake and it was investigated whether this ratio is affected by an additional 5HT intake. It was concluded that the combined intake of ethanol and 5HT augmented the elevation in the urinary 5HTOL/5HIAA ratio compared with ethanol intake alone. This was due to a considerable increase in the relative urinary 5HTOL concentration which, in addition, significantly coincided with adverse physiological effects, such as headache and diarrhoea, thus implying a physiological role of 5HTOL.
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