褪黑素：不止于助眠

褪黑素是哪个器官分泌的呢？在身体里是如何合成和传递的呢？在身体的什么地方起作用呢？大多数临床医生都认为，褪黑素只用于一般睡眠问题，并作为一些与不同癌症相关的合并症的辅助治疗。

但是很多的结肠炎患者通常出现抑郁和睡眠问题——很多信息综合分析会发现，肠道可能才是我们最大的“大脑”。

从荷尔蒙的角度来讲，褪黑素是主要的参与者。

没人会认为褪黑素或任何一种荷尔蒙是万灵药，但需要说明的是，它确实是一种很有潜力的荷尔蒙，在解决各种健康问题方面具有重大作用。如果你认为褪黑素只是睡眠荷尔蒙的话，不妨考虑一下褪黑素的强项：

解决睡眠障碍

减少慢性疼痛甚至神经性疼痛

提高抑郁症患者的生活质量

减少氧化损伤

通过抑制5-LOX和COX-2作为抗炎剂              

提高体液免疫和细胞免疫应答

通过昼夜（来自肠道）和夜间（来自大脑）保持昼夜节律

愈合受损组织

这一切都已经得到了很多文献的证实，但是要真正理解褪黑素的重要性和改善健康的潜力，还应该从褪黑素的生物化学和生理学开始。

关于褪黑素的分泌           

当听到胃肠道合成的褪黑素比松果体高出500倍时，这令人非常惊讶。肠道是我们白天合成褪黑素的主要场所，并且褪黑素的释放随着食物的摄取而显著增加，特别是富含蛋白质、色氨酸含量高的食物，或者色氨酸的摄入。在晚上，没有光的刺激以后，松果体代替肠道成为合成褪黑素的主要场所，褪黑素的释放在凌晨2点左右达到高峰并稳定下降直到苏醒。在皮肤、淋巴细胞、包括支气管在内的全身各种上皮、生殖器官、内皮细胞和甲状腺中均能找到褪黑素合成酶。

褪黑素合成            

从色氨酸途径的前两个步骤需要营养辅因子烟酸、铁、叶酸、锌、B6、镁和维生素C的帮助，从而产生血清素。褪黑素一旦形成，它的多功能结构就允许它很快地穿透附近和远处的组织，产生近乎立即的效果。褪黑素的产生途径始于色氨酸，一种在鸡、鱼、坚果和菠菜等高蛋白食物中发现的必需氨基酸。记住适当的胃酸和胰腺功能是需要分解和同化蛋白质为氨基酸吸收的，这一点很重要。              

循环中的褪黑素被羟基化并与活体中的硫酸盐结合，形成其主要代谢物，如图所示褪黑素6-磺酰氧基(MT6s)，并排泄到尿中。              

褪黑素在哪里起作用？总之，到处都是！

毫不奇怪，褪黑素有它自己的特殊膜受体-MT1，MT2和MT3，发现几乎每一个细胞和组织中，从上皮细胞，神经元到平滑肌。              

在人类体内，褪黑素受体也在几个器官中检测到，包括脑和视网膜、心血管系统、肝和胆囊、肠、肾、免疫细胞、脂肪细胞、前列腺和乳腺上皮细胞、卵巢/颗粒细胞、子宫肌层和皮肤。受体RZR/ROR和膜受体一样遍布全身，可能与其对癌细胞的凋亡作用有关。 

Melatonin’s Importance Is So Much Bigger Than Sleep

I've been up to my elbows in melatonin research for a week now.

I always felt like I had a pretty good working knowledge of where melatonin came from in the body, roughly how it was synthesized, the signals that propagate its production, and where it acts. Like most clinicians, I tended to think of it for sleep problems in general and as an adjunct treatment for some of the comorbidities associated with different cancers.

I was also vaguely aware that there was a physical reason my colitis patients usually presented with depression and sleep problems – the gut really is the bigger of our two brains after all, but I’m not sure I was able to put it all together until this intensive synthesis of information.

Hormonally Speaking, Melatonin is a Major Player

While I’m not ready to say that melatonin or any one hormone is a panacea, I will say it truly is a hormone with far-reaching potential to be a major player in resolving a myriad of health issues. If you are someone who thought melatonin was just that sleep hormone, consider this short list of melatonin’s strengths:

· Resolving sleep disorders

· Decreasing pain in chronic pain conditions, even neuropathic pain

· Improving quality of life in depressed patients

· Reducing oxidative damage

· Acting as an anti-inflammatory agent by inhibiting 5-LOX and COX-2

· Ramping up both humoral and cellular immune responses

· Maintaining the circadian rhythm by day (from the gut) and by night (from the brain)

· Healing damaged tissues

This is all compelling, but to really understand melatonin’s importance and potential for improving health, we should start with what we know about its biochemistry and physiology.

About Melatonin Production

It might be surprising to hear that melatonin is synthesized from L-tryptophan at 500x greater concentrations in the gastrointestinal tract than in the pineal gland 

of the brain. The gut is responsible for most of our daytime synthesis of melatonin and its release increases significantly in response to food intake, particularly protein-rich foods with high tryptophan content, or tryptophan administration. At night, the pineal gland takes over production by responding to light deprivation in the form of a huge surge of melatonin peaking around 2am and dropping steadily until waking. The enzymes for synthesis of melatonin can also be found in the skin, lymphocytes, various epithelia throughout the body including airway passages, reproductive organs, endothelial cells, and in the thyroid.

The 101 on Melatonin Synthesis

The first two steps in the pathway from tryptophan require the help of nutritional cofactors niacin, iron, folate, zinc, B6, magnesium, and vitamin C, resulting in serotonin. Once melatonin is formed, its versatile structure allows it to penetrate nearby and distant tissues very quickly for a near immediate effect.The melatonin production pathway starts with tryptophan, an essential amino acid found in high-protein foods like chicken, fish, nuts and spinach. It’s always important to remember that proper stomach acid and pancreatic function is required to break down and assimilate proteins into amino acids for absorption.

Circulating melatonin is hydroxylated and conjugated with sulfate in the live to form its primary metabolite, melatonin 6-sulfatoxy (MT6s) as shown in the figure, and excreted into urine. 

Where Does Melatonin Act? In Short, Everywhere!

Not surprisingly, melatonin has its own special membrane receptors – MT1, MT2 and MT3 that are found in almost every cell and tissue in the body from epithelia to neurons to smooth muscle.

“In humans, melatonin receptors were also detected in several organs, including brain and retina, cardiovascular system, liver and gallbladder, intestine, kidney, immune cells, adipocytes, prostate and breast epithelial cells, ovary/granulosa cells, myometrium, and skin.” The nuclear melatonin receptors, RZR/ROR, are as ubiquitous throughout the body as the membrane receptors and may be responsible for its apoptotic effects on cancer cells.

References

1. Dai, J, Ram, PT, Yaun, L, Spriggs, LL, Hill, SM. Transcriptional repression of RORa, activity in human breast cancer cells by melatonin. Mol Cell Endocrinol 2001; 176: 111-120.

1. Ekmekcioglu, C. Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother. 2006; 60:97-108.

2. Karasek, M, Winczyk, K. Melatonin in Humans. J Physiol Pharmacol. 2006;57 Suppl 5:19-39.

3. Konturek, SJ, Konturek, PC, Brzozowski, T, Bubenik, GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007; 58 Suppl 6:23-52.