Genes linked to daily flux in drug toxicity

Those so-called “PAR-domain basic leucine zipper transcription factors” (PAR bZip) are known to accumulate in body tissues, including the liver and kidneys, in a highly circadian manner, the researchers said. Circadian refers to biological variations within a roughly 24 hour period.

The findings in mice underscore the crucial role of the body's daily timekeeping system in modulating drug toxicity, the researchers said, and suggest that patients might benefit from treatment regimens that are scheduled accordingly.

The findings also highlight the general importance of circadian clocks to many body functions, said Ueli Schibler of the University of Geneva.

“I think it's fair to say that nearly all physiology has some circadian component,” Schibler said. “People think of jet lag as a sleep disturbance, when that may be the least of the problem,” he added. “All of your organs–from the gastrointestinal system to liver enzymes, for example–depend on clocks.”

Circadian rhythms control rest-activity cycles, heartbeat frequency, body temperature, blood pressure, hormones, and metabolism, among other behavioral and physiological processes.

The circadian timing system of mammals has a hierarchical structure, in that a master pacemaker in the brain synchronizes self-sustaining and cell-autonomous circadian clocks present in virtually all tissues, the researchers said. Drivers of circadian rhythms in peripheral cells–such as the three PAR bZip proteins: DBP, TEF, and HLF–mediate rhythmic physiology by regulating the activity of still other genes.

Earlier studies by Schibler's group found that mice lacking one or two of the PAR bZip proteins exhibit only mild symptoms. Half of those animals lacking all three genes, however, died as a result of epileptic seizures in the first three months of life. Those that survived began to show signs of early aging by the time they reached nine months of age.

To further elucidate the genes' roles in the current study, Schibler's team looked to the liver and kidneys, the two organs in which all three transcription factors are known to have high activity.

By scanning the liver and kidneys of normal mice and PAR bZip-deficient mice for global gene activity patterns, the researchers found differences in many genes known to be involved in defense against chemical compounds and oxidative stress–an indication that the circadian transcription factors normally control the activity of those other detoxifying genes.

Without the normal complement of detox genes, the mice showed evidence of liver damage. Normal mice showed pronounced circadian rhythms in response to the sedative pentobarbitol, they found, clearing the drug faster at night than in the day. In contrast, the mutant mice had severe deficits in sedative clearance at all times and therefore slept much longer following injection. The mutants also suffered much greater harm than normal mice did from two of four chemotherapy drugs.

The inability to handle chemicals properly might explain the animals' rapid aging, the researchers suggest.

“The results provide an important example of the fundamental role that circadian clocks play at the cellular and metabolic level and highlight their dire consequences when disrupted,” wrote Carla Green and Joseph Takahashi in an accompanying commentary. “A deeper understanding of circadian detoxification mechanisms provides a rational basis for optimizing the efficacy of pharmaceutical agents whose toxicity and side effects should be reduced by delivery at optimal times of day.”

The findings reemphasize a principle that scientists had long recognized: sensitivities to chemotherapies and other drugs vary over the course of a day, Schibler agreed. Although rigorous clinical study is needed, patient outcomes might therefore be improved in some cases by delivering chemotherapies, or perhaps other drugs, in accordance with the circadian rhythm.

“Even if patients were made less sick when given chemotherapy at a particular time of day, that could be very important for their well-being,” he said.