Hepatic Melatonin Metabolism Research Articles

Managing Sleep Disturbances in Cirrhosis.

Sleep disturbances, particularly daytime sleepiness and insomnia, are common problems reported by patients suffering from liver cirrhosis. Poor sleep negatively impacts patients' quality of life and cognitive functions and increases mortality. Although sleep disturbances can be an early sign of hepatic encephalopathy (HE), many patients without HE still complain of poor quality sleep. The pathophysiology of these disturbances is not fully understood but is believed to be linked to impaired hepatic melatonin metabolism. This paper provides an overview for the clinician of common comorbidities contributing to poor sleep in patients with liver disease, mainly restless leg syndrome and obstructive sleep apnea. It discusses nondrug and pharmacologic treatment options in these patients, such as the use of light therapy and histamine (H1) blockers.

Phase advance of circadian rhythms in Smith–Magenis syndrome: A case study in an adult man

Melatonin secretion is usually increased during the daytime and decreased at night in Smith–Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24h profiles of core temperature, sleep–wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin.

Sleep-wake abnormalities in patients with cirrhosis

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed.

On the Origin and the Consequences of Circadian Abnormalities in Patients With Cirrhosis

Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior. The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries. There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality. Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.

Melatonin Rhythms in Patients With Cirrhosis

Montagnese, Sara MD, PhD1,3; Middleton, Benita PhD2; Mani, Ali R MD, PhD1; Skene, Debra J PhD2; Morgan, Marsha Y MD1 Author Information

Influence of cigarette smoking on melatonin levels in man

Polycyclic aromatic hydrocarbons in cigarette smoke induce cytochrome P450(CYP)1A2, which is involved in the hepatic metabolism of melatonin (MT). This suggests that habitual smokers may have low serum MT levels during smoking compared with a non-smoking period. We decided to investigate whether this suggestion is correct. Eight habitual smokers were tested on two occasions. They had smoked prior to the first occasion but had not smoked for 7 days prior to the second. Each test was divided into two parts. The first part spanned the night between 2000 hours and 0800 hours. Venous blood samples were collected every second hour during this period for analysis of endogenous serum MT. The second part was performed the subsequent day. At 0930 hours, 25 mg MT was ingested orally, and blood samples for exogenous serum MT analysis were collected every hour between 1000 hours and 1600 hours. Endogenous and exogenous areas under the serum MT-time curve (MT-AUCs) were calculated. Endogenous serum MT-AUCs were similar during the two periods. Oral administration of MT induced supraphysiological levels of serum MT. Moreover, exogenous serum MT-AUCs were significantly smaller before than after smoking abstinence (7.34+/-1.85 versus 21.07+/-7.28 nmol/lxh; P<0.02; means+/-SEM). This investigation shows that exogenous, but not endogenous (at night), serum MT levels are influenced by cigarette smoking. When the MT levels are low, the influence of CYP1A2 levels appears to be less pronounced than when they are high, and the enzyme capacity hugely utilized. These findings implicate that interactions between exogenous MT, and substrates metabolized by CYP1A2, may differ in individuals before and after smoking abstinence.

Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man?

Melatonin (MT) is metabolized in the liver by cytochrome P450 (CYP) 1A2 but its importance for the metabolic process has not been fully elucidated. Therefore, the objective of this investigation was to study whether patients with different CYP1A2 activity would have different nocturnal serum MT levels. For that purpose serum MT concentrations were determined every second hour during the night in 12 healthy subjects and their MT areas under the curve (MT-AUCs) were calculated. Caffeine (CA) clearance was determined in advance. It is generally accepted that CA clearance reflects CYP1A2 activity. This made it possible to evaluate whether a relationship prevails between endogenous MT-AUCs and CYP1A2 activity. If CYP1A2 is of importance for the metabolism of MT one would expect to find an inverse correlation between the MT-AUCs and the CA clearance. However, such correlation did not exist in the current study (Rs=-0.021, NS). Since endogenous MT-AUC is dependent not only on MT elimination by CYP1A2 but also on MT secretion, it is possible that an increased MT secretion counter-balances an increased hepatic MT metabolism. If so, this could explain why the MT-AUCs and the CA clearance values were not inversely correlated in this study.

Contribution of CYP1A2 in the hepatic metabolism of melatonin: studies with isolated microsomal preparations and liver slices.

The objective of the present studies was to define the enzyme systems catalysing the 6-hydroxylation of melatonin, by monitoring the levels of 6-sulphatoxymelatonin in rat hepatic postmitochondrial preparations and in precision-cut liver slices. Melatonin 6-hydroxylase activity was localized in microsomes and was supported by NADPH, but not NADH. Treatment of rats with beta-naphthoflavone more than tripled 6-sulphatoxymelatonin formation from melatonin, but gave rise only to a moderate increase (25%) in the sulphate conjugation of 6-hydroxymelatonin. Treatment of rats with phenobarbitone, acetone, dexamethasone and clofibrate did not increase 6-sulphatoxymelatonin generation when either melatonin or 6-hydroxymelatonin served as substrates. Of a number of cytochrome P450 inhibitors investigated, only furafylline inhibited markedly the conversion of melatonin to 6-sulphatoxymelatonin without any concomitant effect on the sulphoconjugation of 6-hydroxymelatonin. When liver slices were incubated with melatonin, treatment of rats with beta-naphthoflavone, and to a lesser extent phenobarbitone, elevated the levels of 6-sulphatoxymelatonin in the culture medium. No such increase was seen when slices from beta-naphthoflavone-treated rats were incubated with 6-hydroxymelatonin, whereas a modest increase was seen with slices from phenobarbitone-treated rats. Treatment of rats with acetone, dexamethasone or clofibrate failed to modulate the levels of 6-sulphatoxymelatonin generated from either melatonin or 6-hydroxymelatonin. Molecular modelling analysis revealed that melatonin had a high area/depth(2) ratio, displayed characteristics of CYP1A2 substrates and could be readily accommodated into the human CYP1A2 active site in a position favouring 6-hydroxylation. Collectively, all the above data provide strong experimental evidence that CYP1A2 is an important catalyst of the 6-hydroxylation of melatonin.

Psoralens in association with seasonal affective disorder

The pathogenesis of seasonal affective disorder (SAD) has been attributed to abnormal melatonin metabolism. Perorally administered psoralens increase the daytime levels of melatonin via the competitive inhibition of hepatic melatonin metabolism. Some findings among SAD patients are parallel to those observed after the administration of a psoralen in healthy subjects. It is hypothesized that there may be a circulating psoralen-like substance which affects SAD patients under a low level of illumination. Exposure to bright light during the daylight period would normalize the abnormal effect independently of the season.

Direct radioimmunoassay of 6-sulfatoxymelatonin in plasma with use of an iodinated tracer

We describe here a direct a radioimmunoassay (RIA) for the determination of 6-sulfatoxymelatonin (aMT6s) in plasma, with iodinated aMT6s as tracer. The aMT6s antiserum was raised in rabbit by immunization with a bovine serum albumin conjugate, giving negligible cross-reactivities for related compounds. The low limit of detection (15 pmol/L) allowed a direct assay that required only a 100-microL plasma sample. Dilutions of plasma and of synthetic aMT6s gave the same parallel response in the RIA. A preliminary study showed a circadian variation in healthy volunteers, with mean concentrations ranging from 52 (at 1600-2100 h) to 378 pmol/L (at 0400 h), whereas this rhythm was abolished in pinealomectomized patients. After administration of melatonin orally, or by infusion, the aMT6s concentrations in plasma concorded with previous data on aMT6s production and pharmacokinetics, with aMT6s being cleared from plasma more slowly than melatonin. This assay should have practical application in the development of new pharmaceutical formulations that minimize the hepatic metabolism of melatonin.

Chlorpromazine inhibition of melatonin metabolism by normal and induced rat liver microsomes.

Hepatic metabolism of melatonin has been investigated. Melatonin was converted in vitro by rat liver microsomes to 6-hydroxymelatonin and to a lesser extent to N-acetylserotonin. Induction with phenobarbitone caused a fourfold increase in the formation of the minor product with little effect on 6-hydroxymelatonin production or melatonin turnover. In contrast, benzpyrene induction caused a dramatic increase in melatonin turnover but the formation of both metabolites, particularly 6-hydroxymelatonin was significantly reduced. This suggests that an alternative inducible pathway is involved in melatonin catabolism. Chlorpromazine, which elevates plasma melatonin in man and rat, significantly reduced melatonin turnover and reduced the formation of both metabolites in control and phenobarbitone induced microsomes. With benzpyrene induction, chlorpromazine inhibited melatonin turnover but in this group, 6-hydroxymelatonin concentrations were higher than controls. It is thus proposed that the drug preferentially inhibits the alternative benzpyrene inducible isozyme rather than the melatonin hydroxylase.