The antioxidant and possible pro-oxidant effects of melatonin and related indoleamines (tryptophan, serotonin, N-acetylserotonin, and 5-methoxytryptamine) were studied in vitro. In two model membrane systems, i.e., phospholipid liposomes and rat erythrocytes, lipid peroxidation induced by Fe2+ and H2O2, respectively, were reduced by the tested indoleamines except for tryptophan. The 5-hydroxy-indoleamines, serotonin, and N-acetylserotonin exhibited pro-oxidant actions in the bleomycin assay by reducing Fe3+ to Fe2+, which leads to DNA damage. The 5-methoxy-indoleamines, melatonin and 5-methoxytryptamine, were devoid of any pro-oxidant actions in this assay. Serotonin, but not N-acetylserotonin, scavenged the superoxide anion. None of the indoleamines tested had any reactivity towards H2O2. All the indoleamines, including tryptophan, were, however, shown to react with hypochlorous acid. These findings support an antiperoxidative and antioxidant action of melatonin which is devoid of pro-oxidant effect on non-lipid substrates.
The effect of melatonin on cholesterol metabolism in the rat was investigated in the dietary and hypothyroid models of hypercholesterolemia. In normal and dietary hypercholesterolemia (induced by 1% cholesterol, 0.5% bile acid), melatonin treatment (12.5mg/kg i.p.) reduced total serum cholesterol concentration and total low density lipoprotein (VLDL+LDL) cholesterol. The protective action of melatonin was manifested only following the induction of cholesterolemia in such animals. Enhanced catabolism of cholesterol to bile acids is likely involved as shown by an increase in fecal bile acid excretion following melatonin treatment. Incorporation of 1-14C acetate into sterols was unaffected by melatonin treatment which suggests its lack of influence on sterol biosynthesis. In secondary hypercholesterolemia (hypothyroidism induced by 2-thiouracil), melatonin exerted a beneficial effect by increasing the HDL/total LDL cholesterol ratio. These findings suggest that the hypocholesterolemic effect of melatonin may work through the augmentation of endogenous cholesterol clearance mechanisms. This is accompanied by the lowering of the cholesterol fraction associated with low density lipoproteins.
The patterns of plasma melatonin, gonadotropins, sex steroids and prolactin were studied in anovulatory infertile females undergoing ovulation induction with hMG/hCG. Melatonin levels were found to fluctuate during the menstrual cycle of these subjects with a nadir at mid-cycle and peak occurring at the early follicular/late luteal phases of the cycle (p < 0.05). Melatonin correlated negatively with estradiol during the follicular phase (r = –0.5180, p < 0.05) and positively with LH (5 + 0.6321, p < 0.05) in the luteal phase, respectively. Correlational analyses by partial and multiple correlations suggest that the effects of estradiol and LH on melatonin in the follicular phase are interdependent whereas the effect of LH on melatonin in the luteal phase is independent of the effects of other hormones. The results suggest that hormonal interactions and phases of the cycle are important variables contributing to the fluctuations in melatonin levels during the menstrual cycle.
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