Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Genes linked to daily flux in drug toxicity

06.07.2006
New findings in the July, 2006, Cell Metabolism, published by Cell Press, may help to explain daily fluctuations in the ability to detoxify chemical substances, including chemotherapy drugs and sedatives. Researchers report that three related proteins drive the activity of genes involved in neutralizing toxins and breaking down drugs.

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.

Heidi Hardman | EurekAlert!
Further information:
http://www.cell.com
http://www.cellmetabolism.org

More articles from Life Sciences:

nachricht Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>