Also see:
Estrogen Increases Serotonin
Hypothyroidism and Serotonin
Omega -3 “Deficiency” Decreases Serotonin Producing Enzyme
Enzyme to Know: Tryptophan Hydroxylase
Tryptophan, Sleep, and Depression
Carbohydrate Lowers Free Tryptophan
Gelatin > Whey
Serotonin, Fatigue, Training, and Performance
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Serotonin and Melatonin Lower Progesterone
Role of Serotonin in Preeclampsia
Maternal Ingestion of Tryptophan and Cancer in Female Offspring
Melatonin Lowers Body Temperature
Pellagra occurs about twice as often in women as in men, and this is because estrogen activates an enzyme that alters metabolism of tryptophan, blocking the formation of niacin. The alternative products include the excitotoxin, quinolinic acid, and some carcinogens.
Progesterone inhibits the activity of that enzyme. Progesterone also lowers brain serotonin (Izquierdo, et al., 1978), decreases the excitatory carcinogens (Moursi, et al., 1970) and increases the formation of niacin (Shibata, et al., 2003) The polyunsaturated fats, DHA, EPA, and linoleic acid activate the conversion of tryptophan to quinolinic acid (Egashira, et al., 2003, 2007), and inhibit the formation of niacin (Egashira, et al., 1995). -Ray Peat, PhD
Pharmacol Res Commun. 1978 Jul;10(7):643-56.
Role of ACTH on the effect of medroxyprogesterone in brain stem serotonin.
Izquierdo JA, Savini C, Borghi E, Rabiller G, Costas S, Justel E.
A clinical study with 361 female rats was conducted to elucidate the mechanism whereby MPA (medroxyprogesterone acetate) lowers 5-HT/5-HIAA ratio in the brain area and the possible role of serotoniergic mechanisms. In addition, the participation of MAO (monoamino oxidase) system and the effects of some steroids were studied in order to establish a relationship between chemical structure and activity. The effects of the following steroids were studied: MPA (medroxyprogesterone acetate), melengestrol acetate, chlormadinone, pregnenolone, -methyl pregnenolone, DOCA, acetoxi-progesterone, and ACTH (synacthen). Effects of these substances on LTP (liver tryptophan pyrrolase) activity, total and free plasma and brain stem Trp (tryptophan), and the 5HT and 5HTAA content in brain stem are tabulated. Of all the substances, only MPA and melengestrol acetate significantly raised LTP activity and both also lowered 5-HT content of brain stem. The high levels of ACTH in the blood of the adrenalectomized rats, as in those under fasting conditions, antagonized MPA effects. To further test this seeming result, ACTH and ACTH-MPA were injected into another group of animals. The ACTH not only increased plasma corticosterone but also antagonized the effect of MPA on the 5-HT content of brain stem. The study did not identify a relationship between chemical structure of the steroids studied and effects observed.
Biosci Biotechnol Biochem. 1997 Jul;61(7):1200-2.
Effects of sex hormones on the metabolism of tryptophan to niacin and to serotonin in male rats.
Shibata K, Toda S.
It is known that deaths attributable to pellagra, which is considered to be a disease caused by the disturbance of tryptophan metabolism, have been approximately two-fold higher in women than in men. We investigated the effects of the administration of female and male sex hormones on the contents of tryptophan and such metabolites as serotonin, nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, and on the conversion ratio of tryptophan to niacin in male rats. Feeding a diet containing estrone or testosterone had no effect on the concentrations of tryptophan and serotonin in the blood and brain, or on the concentration of 5-hydroxyindole-3-acetic acid in the brain. On the contrary, feeding a diet containing estrone caused to a decrease in the urinary excretion of nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, and of the conversion ratio of tryptophan to niacin when compared with the control rats. Feeding a diet containing testosterone had no effect on any parameter. We postulate from these findings that the cause of higher pellagra deaths in women than in men is attributable to the decrease in the formation of niacin from tryptophan, but not in the formation of serotonin by the female hormone. It seems likely that female sex hormones inhibit the synthesis of niacin from tryptophan, and that women, especially during pregnancy, will be more at risk to pellagra than are men.
Bull World Health Organ. 1970;43(5):651-61.
The influence of sex, age, synthetic oestrogens, progestogens and oral contraceptives on the excretion of urinary tryptophan metabolites.
Moursi GE, Abdel-Daim MH, Kelada NL, Abdel-Tawab GA, Girgis LH.
The excretion of urinary tryptophan metabolites was studied in normal and postmenopausal women and in women taking norethindrone and ethinyl estradiol, singly and in combination. The results showed that the altered tryptophan metabolism found in the preovulatory phase of the cycle and in postmenopausal women was the result of an interaction between Vitamin-B6 and endogenous sex hormones. During the preovulatory phase, endogenous estradiol disrupted the normal activity of the Vitamin-B6-dependent quinolinic acid decarboxylase, which resulted in the accumulation of bladder carcinogens in urine. During the postovulatory phase, endogenous progesterone and the production of metabolites antagonized this effect. Administration of naturally occurring progesterone and of ethinyl estradiol, alone and in combination with norethindrone, was able to counter the interaction between Vitamin-B6 and endogenous estradiol. It is suggested that the cyclic excretion pattern of endogenous bladder carcinogens in young, nonpregnant women may contribute, in part, to the low incidence of bladder cancer in women.
Br J Nutr. 1984 Mar;51(2):219-24.
Inhibition of tryptophan metabolism by oestrogens in the rat: a factor in the aetiology of pellagra.
Bender DA, Totoe L.
The effect of the administration of oestrone sulphate on tryptophan metabolism has been assessed in rats in order to determine whether and to what extent inhibition of tryptophan metabolism by oestrogens may be a factor in the aetiology of pellagra, and might explain the reported twofold excess of females over males in many outbreaks of pellagra. Feeding ovariectomized rats for 1 week on a diet containing 15 mg oestrone sulphate/kg led to significant inhibition of kynurenine hydroxylase (EC 1.14.13.9), kynureninase (EC 3.7.1.3) and 3-hydroxyanthranilate oxidase (EC 1.13.11.6). There was also a significant increase in plasma tryptophan, suggesting decreased activity of tryptophan oxygenase (EC 1.13.11.11). This inhibition of tryptophan metabolism will result in a considerable reduction in the synthesis of the nicotinamide nucleotide coenzymes (NAD and NADP) from tryptophan. When ovariectomized rats were maintained for 4 weeks on a diet providing no preformed niacin and only a marginally adequate amount of tryptophan (1030 mg/kg), the addition of sulphate to the diet led to a significant reduction in the liver content of nicotinamide nucleotides and the urinary excretion of the end-product of NAD metabolism, N1-methyl nicotinamide. It is suggested that when the diet is only marginally adequate in tryptophan and niacin, inhibition of tryptophan metabolism by endogenous or administered oestrogens may be an additional factor in the development of pellagra.
Br J Nutr. 1982 May;47(3):609-14.
Effects of oestrogen administration on vitamin B6 and tryptophan metabolism in the rat.
Bender DA, Tagoe CE, Vale JA.
1. In order to assess the effects of oestrogens on the metabolism of tryptophan and vitamin B6, ovariectomized rats have been maintained on diets providing known amounts of tryptophan, nicotinamide and vitamin B6. They received oestrone sulphate, 210 micrograms/kg body-wt per d, either incorporated in the diet for 8 weeks, or by daily intraperitoneal injection for periods of 1-3 d. 2. Oestrone sulphate administration caused a slight reduction in the concentration of pyridoxal phosphate in plasma. It had no effect on the concentration of pyridoxal phosphate in liver or kidney, the urinary excretion of 4-pyridoxic acid, the activation of erythrocyte aspartate aminotransferase (L-aspartate:2-oxo-glutarate aminotransferase, EC 2. 6. 1. 1) by incubation with added pyridoxal phosphate, or the activity of pyridoxal oxidase (aldehyde:oxygen oxido-reductase, EC 1.2.3.1) in the liver. 3. Oestrone sulphate administration caused an increase in the urinary excretion of kynurenine and a reduction in the activity of liver kynureninase (L-kynurenine hydrolase, EC 3.7.1.3). It had no effect on the urinary excretion of N1-methyl nicotinamide or the concentrations of nicotinamide nucleotides in blood, liver or kidney. 4. There was a considerable excess of the apoenzyme of kynureninase in the liver. Incubation of liver homogenates with added pyridoxal phosphate led to a 4- to 5-fold increase in activity. 5. We conclude that there is no evidence of any significant effect of oestrogens on vitamin B6. It is suggested that abnormalities of tryptophan metabolism in women receiving oestrogens, which have been widely attributed to drug-induced vitamin B6 depletion, can be accounted for by inhibition of kynureninase by oestrogen metabolites.
Adv Exp Med Biol. 2003;527:435-41.
Increase in conversion of tryptophan to niacin in pregnant rats.
Shibata K, Fukuwatari T, Murakami M, Sasaki R.
There is the report that the deaths by pellagra in women is approximately twofold excess that in men. In the present experiment, in order to clarify a factor in the etiology of pellagra in female and to get basic information how much niacin should be supplemented in pregnant state, we investigated the effects of pregnant on the metabolism of tryptophan to niacin in rats. The daily urine samples were collected from day -17 and day +6 (the delivery day was designated as day 0) and the intermediates of tryptophan to niacin were measured. The metabolites such as kynurenic acid, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide were increased with progress in pregnant and returned to normal levels after the delivery. The catabolism of tryptophan is accelerated during pregnancy, indicataing that pregnancy would not be an etiology of pellagra and no niacin supplement needs but tryptohan supplement would need.
Biochim Biophys Acta. 2004 Nov 8;1686(1-2):118-24.
Differential effects of dietary fatty acids on rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression.
Egashira Y, Murotani G, Tanabe A, Saito K, Uehara K, Morise A, Sato M, Sanada H.
Hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD; formerly termed picolinic carboxylase) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis and the generation of quinolinate (quinolinic acid) from tryptophan. Quinolinate is a potent endogenous excitotoxin of neuronal cells. We previously reported that ingestion of fatty acids by rats leads to a decrease in their hepatic ACMSD activity. However, the mechanism of this phenomenon is not clarified. We previously purified ACMSD and cloned cDNA encoding rat ACMSD. Therefore, in this study, we examined the differential effect of fatty acids on ACMSD mRNA expression by Northern blot. Moreover, we measured quinolinic acid concentration in rats fed on fatty acid. When diets containing 2% level of fatty acid were given to male Sprague-Dawley rats (4 weeks old) for 8 days, long-chain saturated fatty acids and oleic acid did not affect ACMSD mRNA expression in the liver. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) strongly suppressed the liver ACMSD mRNA expression. In rats fed with high linoleic acid diet for 8 days, serum quinolinic acid was significantly increased as compared with the rats fed on a fatty acid-free diet under the condition of the approximately same calorie ingestion. These results suggest that the transcription level of ACMSD is modulated by polyunsaturated fatty acids, and suppressive potency of ACMSD mRNA is n-3 fatty acid family>linoleic acid (n-6 fatty acid)>saturated fatty acid. Moreover, this study provides the information that a high polyunsaturated fatty acid diet affects the production of quinolinic acid in serum by suppressing the ACMSD activity.
Int J Vitam Nutr Res. 2007 Mar;77(2):142-8.
Dietary protein level and dietary interaction affect quinolinic acid concentration in rats.
Egashira Y, Sato M, Saito K, Sanada H.
During tryptophan-niacin conversion, hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis. ACMSD activity is greatly affected by many factors such as nutritional status and disease. The tryptophan catabolite quinolinic acid has been reported to be associated with the pathogenesis of various disorders and is a potential endogenous toxin. However the effects of dietary protein levels or dietary interaction between protein levels and fatty acid type to this process have not been investigated and are still unknown. In this study, we examined whether dietary protein level, fatty acid type, namely saturated fatty acid and polyunsaturated fatty acid, and their interaction affect serum quinolinic acid concentration in rats. Male Sprague-Dawley rats (4-weeks old) were fed with 20% casein + 10% stearic acid diet (20C10S), 20% casein + 10% linoleic acid diet (20C10L), 40% casein + 10% stearic acid diet (40C10S), or 40% casein + 10% linoleic acid diet (40C10L) for 8 days, and serum quinolinic acid concentration and ACMSD activity were determined. Serum quinolinic acid concentration was significantly increased in the 40C10L group compared with other three groups. There was also the negative correlation between the sum of liver and kidney ACMSD activities, and serum quinolinic acid concentration per tryptophan intake (r = 0.8209, p < 0.01). Increased serum QA concentrations are probably due to a decreased ACMSD activity.
Comp Biochem Physiol A Physiol. 1995 Aug;111(4):539-45.
Effect of dietary linoleic acid on the tryptophan-niacin metabolism in streptozotocin diabetic rats.
Egashira Y, Nakazawa A, Ohta T, Shibata K, Sanada H.
To make clear the mechanism of change of tryptophan-niacin metabolism in diabetic rats, we investigated the effect of dietary linoleic acid on the tryptophan-niacin metabolites and the activity of liver, alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), a key enzyme of tryptophan-niacin metabolism, in streptozotocin diabetic rats. Moreover, we investigated the involvement of linoleic acid in the induction of hepatic ACMSD activity by streptozotocin diabetes. In diabetic rats, the sum of urinary excretion of nicotinamide, N1-methylnicotinamide (MNA), N1-methyl-2-pyridone-5-carboxamide (2-Py) and N1-methyl-4-pyridone-3-carboxamide (4-Py) was higher in the fat free diet group than in the linoleic acid group, that was accompanied by the increase of tryptophan intake and reduction of body weight in the fat free diet group. In diabetic rats, hepatic ACMSD activity was higher in the fat free diet group than in the linoleic acid group. The results indicated that the induction of hepatic ACMSD activity by diabetes was not due to removal of the suppressive effect of the linoleic acid on the enzyme. In the diabetic+insulin group, hepatic ACMSD activity was significantly lower than in the diabetic group.
