Genes Linked To Daily Flux In Drug Toxicity

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Genes Linked To Daily Flux In Drug Toxicity

http://www.medicalnewstoday.com/medicalnews.php?newsid=46654

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 ph 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.

###

The researchers include Frederic Gachon of the University of Geneva

in Geneva, Switzerland and Institut de Genetique Humaine, CNRS UPR

1142 in Paris, France; Fabienne Fleury Olela, Olivier Schaad,

Descombes, and Ueli Schibler of the University of Geneva in Geneva,

Switzerland.

This research was supported by the Swiss National Science Foundation

(through an individual research grant to U.S. and the NCCR program

Frontiers in Genetics), the State of Geneva, the Louis Jeantet

Foundation of Medicine, and the Bonizzi-Theler Stiftung.

Gachon et al.: " The circadian PAR-domain basic leucine zipper

transcription factors DBP, TEF, and HLF modulate basal and inducible

xenobiotic detoxification. " Publishing in Cell Metabolism 4, 25-36,

July 2006 DOI 10.1016/j.cmet.2006.04.015

http://www.cellmetabolism.org/