Circadian rhythms: mechanisms and therapeutic implications.
The mammalian circadian system is organized in a hierarchical manner in that a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain's hypothalamus synchronizes cellular circadian oscillators in most peripheral body cells. Fasting-feeding cycles accompanying rest-activity rhythms are the major timing cues in the synchronization of many, if not most, peripheral clocks, suggesting that the temporal coordination of metabolism and proliferation is a major task of the mammalian timing system. The inactivation of noxious food components by hepatic, intestinal, and renal detoxification systems is among the metabolic processes regulated in a circadian manner, with the understanding of the involved clock output pathways emerging. The rhythmic control of xenobiotic detoxification provides the molecular basis for the dosing time-dependence of drug toxicities and efficacy. This knowledge can in turn be used in improving or designing chronotherapeutics for the patients who suffer from many of the major human diseases.
Levi
Francis
F
INSERM U776, Unité de Chronothérapie, Service de Cancérologie, Hôpital Paul Brousse et Université Paris XI, 94800 Villejuif, France. levi-f@vjf.inserm.fr
Schibler
Ueli
U
D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D019454:Chronotherapy; D002940:Circadian Rhythm / Q000502:physiology*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D015262:Xenobiotics / Q000009:adverse effects / Q000493:pharmacokinetics*
D015262:Xenobiotics