Metabolism of melatonin : With focus on the influence of cytochrome P4501A2

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: Melatonin (MT) regulates circadian rhythms. It is produced by pinealocytes. Their function is regulated by light. MT enters the blood stream by passive diffusion. It is primarily metabolized in the liver by 6hydroxylation followed by sulphate and/or glucuronide conjugation with 6-sulphatoxy-MT being the major urinary metabolite. Great efforts have been spent on studies dealing with properties and effects of MT. Less interest has been given to its metabolism. Aims: To study the metabolism of MT, and to find the cytochrome P450 (CYP)-enzyme(s) which catalyzes the hydroxylation of MT in the liver. Subjects and methods: 21 women and 18 men, all healthy, were investigated during the night - some of them also during the day. Blood samples were collected repeatedly for analysis of MT. Serum levels of MT were measured with radioimmunoassay or with liquid chromatography mass spectrometry. Studies: 1) When this project commenced it was known that fluvoxamine (FLU) augments MT-levels. However, underlying mechanisms were unclear. For that reason healthy individuals were given placebo, and two different selective serotonin re-uptake inhibitors (SSRIs) - FLU and citalopram (CIT) - on three separate occasions. 2-3) The CYP1A2 activity varies considerably between individuals. In these studies endogenous and exogenous serum levels of MT were measured in previously CYP1A2-phenotyped subjects, and tested for correlation with the CYP1A2 activity. 4) Caffeine is primarily metabolised by CYP1A2. Caffeine and placebo were given on two separate occasions to healthy subjects. Endogenous serum levels of MT were then compared. If CYP1A2 is involved in the metabolism of MT, serum levels of MT should increase more after ingestion of caffeine than after placebo. 5) Tobacco smoke induces CYP1A2. In habitual smokers endogenous and exogenous serum levels of MT were compared before and after one week of smoke abstention. Results and discussion: 1) Endogenous serum levels of MT increased much more after FLU than after CIT, but were similar after CIT and placebo. Since FLU inhibits CYP1A2, these results imply, that CYP1A2 is involved in the metabolism of MT. They also demonstrate that the FLU-induced increase of MT is not a classeffect, which is seen after SSRI-drugs. 2) Low endogenous serum levels of MT and the CYP1A2 activity were not inversely correlated, probably because the enzyme capacity was not very utilized when the serum concentrations of MT was low. 3) High exogenous serum levels of MT were inversely correlated with the CYP1A2 activity. This could be an effect caused by high saturation of the catalytic binding-sites on CYP1A2. 4) Serum levels of MT increased more after caffeine than after placebo. Substrate interaction is probably the mechanism underlying this result. 5) Habitual smokers had lower exogenous serum levels of MT during smoking than after smoke abstention, but their endogenous serum levels of MT were similar on these two occasions. It may well be that smoke- induced enzyme-induction, causing changed serum levels of MT, is easier to discern if the enzyme is very utilized than if it is less extensively utilized. Conclusions: CYP1A2 catalyzes the hydroxylation of MT in the liver, and serum levels of MT can therefore be affected in metabolic situations influenced by CYP1A2. When judging endogenous or exogenous serum levels of MT, CYP1A2-interactions should be considered.

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