Circadian rhythm metabolism

The dose and frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors and nongenetic variables, such as age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows summarizes the most important of these variables. 

Melatonin (lV-acetyl-5-methoxytryptamine) is a neuro-hormone secreted by the pineal gland from the amino acid precursor [,-tryptophan. Its endogenous secretion is photosensitive and has a circadian rhythm—plasma melatonin concentrations are highest at night in both diurnal and nocturnal animals, and fall with age (1). The nocturnal melatonin peak coincides with a drop in body temperature and increased sleepiness in healthy humans. Oral melatonin has a short half-life (30-50 minutes) and extensive first-pass metabolism. Its clearance is reduced in severe liver disease (2). 

Once a chemical enters the body of animal or human, it undergoes metabolic reaction. A host of factors modulate the reaction rate and the induction of toxicological effects. These factors have been termed intrinsic factors and include animal species, gender, age, nutritional status, pregnancy, other health status, and circadian rhythms. In addition, there are certain extrinsic factors (e.g., physicochemical properties of chemicals, solvent or vehicle, route of exposure, temperature, and humidity) during exposure to chemicals that also influence the effect of a test chemical. We shall discuss these factors in greater detail. 

Another well-recognised complication in the study of cestode metabolism is the fact that a number of species (e.g. Echinococcus granulosus, Hymenolepis diminuta, Taenia crassiceps) have now been shown to exist as complexes of different strains, which may, often quite considerably, differ in their biochemistry. This important aspect is considered, in depth, in Chapters 5, 6 and 10. Furthermore, there is evidence that parasites from different host species or different strains of host show differences in metabolism, and the sex and circadian rhythm of the host can also influence the biochemistry of the parasite under study (59). 

Focusing our attention on the serotonin branch of Figure 20.21, it is seen that the initial hydroxylation reaction requires tetrahydrobiopterin, which was introduced in Chapter 16 and is discussed further here. Serotonin per se is a neurotransmitter, and it can give rise to melatonin in the pineal gland. Melatonin is synthesized at night, and is believed to be associated with the phenomenon of circadian rhythms. Serotonin is metabolized to 5-hydroxyindoleacetic acid, which is excreted in the urine. Normal 5-hydroxyindoleacetic add excretion is about 7 mg/day, whereas in carcinoid tumor patients, this may be as high as 400 mg/day. Carcinoid is an intestinal tumor that may metastasize into the liver. 

In many species, xenobiotic metabolism exhibits circadian and seasonal cycles. In wild populations, these cycles may be related to many factors including day length, diet, breeding cycles, and temperature. Since most laboratory animals are kept under controlled environmental conditions, they do not display seasonal changes in metabolism. However, they do exhibit circadian rhythms in activity and endocrine function... 

Melatonin is an indole-derived anterior pituitary hormone that causes downstream inhibition of a-MSH-induced melanogenesis. Melatonin is antiamnesic, synchronizes circadian and circannual rhythms and is metabolized to 5-methoxytryptamine. Melatonin acts via GPCRs MT1 and MT2 (which both couple through Gai and cAMP decrease). MT1 may also couple via Gao and Gaq to activate PLC (and hence increase cytosolic Ca2+) and via G Gy activation of PLA2. Melatonin can further interact with nuclear receptor superfamily orphan retinoid receptors RZR/ROR. Melatonin fluctuates with a circadian rhythm and is elevated in blood during the night. Melatonin is accordingly of social importance in relation to shift work and jet-lag. Melatonin and 5-methoxytryptamine occur in some plants (Table 5.8). 

Riboflavin has a central role as a redox coenzyme in energy-yielding metabolism and a more recently discovered role as the prosthetic group of the cryptochromes in the eye - the blue-sensitive pigments that are responsible for day-length sensitivity and the setting of circadian rhythms. 

Circadian rhythms exist in cell metabolism and proliferation and those of leukaemic cells differ from normal leucocytes. Evidence is increasing that the time of day at which therapy is administered does iirfluence the outcome for example, maintenance chemotherapy of some leukaemias is more effective if given in the evening (chronomodulation). 

The liver ensures that approximately 70 partial functions within 12 major metabolic areas proceed either continuously or in biological (e.g. circadian) rhythms, or vary according to specific requirements, (s. tab. 3.1)... 

Xenobiotic metabolism has been observed to vary with circadian and seasonal cycles in wild animals. These correspond to variations in Phase I and Phase II enzyme production during breeding cycles. In humans, shift workers have been found to have increased rates of heart disease and metabolic illness. This has been attributed to the finding that one-fifth of liver enzymes show circadian rhythms. 

Gene transcription Cell-cycle progression Organ formation Circadian rhythms Inflammatory response Tumor suppression Cholesterol metabolism Antigen processing... 

Pineal body and circadian rhythms - The pineal body is rich in biogenic amines, and the formation and metabolism of HT, melatonin and other indoles was noted above " > 88,41 j g found there in the... 

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