114 The daytime-dependent differences

in drug sensitivity can be remarkable. For example, In mice the dose at which 50% of the animals die after the administration of the anticancer drug 5-fluorouracil is twice higher at ZT05 as compared with ZT17.116 Moreover, the probability of succumbing to a single constant dose of tumor necrosis factor alpha Injected at regular Intervals during the day oscillates approximately 10-fold.117 All In all, day time dependent toxicity has been established for over 30 anticancer Inhibitors,research,lifescience,medical therapeutics In laboratory rodents.117 Owing to the availability of mutant mouse models for various core clock and clock-controlled genes, some genetic circuits linking circadian oscillators to xenoblotic detoxification could be deciphered. One such pathway, Involving DBP, HLF, and TEF, the three members of the PAR bZIp transcription Inhibitors,research,lifescience,medical factor, is Illustrated In Figure 4. In liver, kidney, and small Intestine, the accumulation of all three of these proteins follows a robust circadian rhythm that Is controlled both on the transcriptional and post-translational level.93, 119-121 DBP, TEF, and HLF must execute partially overlapping functions, Inhibitors,research,lifescience,medical since disruption of only one or two of the genes encoding these transcription factors does not result In strong phenotype changes under laboratory conditions.92, 93, 122, 123 However, mice deficient In all

three PAR bZlp proteins age at an accelerated rate and die prematurely. Genome-wide transcrlptome profiling revealed that these transcription factors govern the circadian accumulation and/or activity of circadian regulators and enzymes Involved In xenobiotic detoxification pathways (Figure 4). As a consequence, PAR bZip-deficient mice are exquisitely sensitive to xenobiotic Inhibitors,research,lifescience,medical compounds such as barbiturates and anticancer drugs.123 Figure 4. A clock output pathway regulating

circadian xenobiotic detoxification. The SCN master pacemaker synchronizes circadian oscillators in peripheral organs, such as liver, Inhibitors,research,lifescience,medical 5-HT receptor drugs kidney and small intestine. The molecular signaling pathways involved in this process … As reported by Antoch and colleagues, Rebamipide mice homozygous for a Bmal1 null allele or a Clock dominant-negative mutant allele also display Impaired resistance against xenobiotic drugs such as cyclophosphamide.124 These authors concluded that daytime dependent responses of the drug targets (eg, the hematopoietic system), rather than circadian drug metabolism, was the rate-limiting parameter in circadian sensitivity to cyclophosphamide. Clearly, more experiments with additional drugs will be required to examine the entire spectrum of mechanisms involved in the circadian sensitivity to xenobiotics. Whatever their outcome will be, such studies will hopefully contribute to the awareness that the time of day should be taken into consideration when designing regimens for therapeutic treatments.