Sci. Aging Knowl. Environ., 3 December 2003
Just a Little Bit
A pinch of growth hormone gives young rats an old collection of drug-processing enzymes
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2003/48/nw163
Key Words: CYP isoform interpulse period nadir
Cholesterol fighters, heart medicine, arthritis pills--as people age, they need more and more medications to battle an escalating number of ailments. But in the elderly, drugs often lose effectiveness or gain toxicity. Changes in the production of drug-deactivating machinery might be partly to blame. A new study shows that nudging growth hormone (GH) concentrations gives young rats an old complement of enzymes.
The liver contains a family of enzymes called cytochrome P450s that neutralize drugs and other foreign compounds. Without them, one Valium tablet might permanently sedate a patient, says physiologist Bernard Shapiro of the University of Pennsylvania School of Veterinary Medicine in Philadelphia. The elderly are especially susceptible to drug side effects, he says, perhaps because of changes in the proportion of different cytochrome P450s. Researchers have used rats to investigate this phenomenon and have found that each sex generates its own group of cytochrome P450 enzymes. As male rats age, they stop producing the male-specific enzymes and start producing the female ones. That change might underlie age-related deficits in drug effectiveness for the male animals.
GH activates cytochrome P450 genes, so Shapiro wondered whether age-related changes in GH release underlie the shift in male rats. The pituitary gland spurts GH in daily pulses; as organisms age, the magnitude of those pulses declines. Shapiro's group previously showed that reducing the peaks by 95% in rats didn't alter cytochrome P450 production. In the new work, Shapiro and colleague Ravindra Dhir investigated the impact of other aspects of GH release.
First, the researchers measured blood GH concentrations in young and old rats at 10-minute intervals. In young males, GH concentrations spiked several times per day, dropping to nearly zero between the peaks. In old males, the height of the spikes diminished but the quantity released between the peaks rose, compared to young animals. Young and old females carried discernible and similar GH amounts between peaks, and females exhibited a much less dramatic change in cytochrome P450 profiles with age than males did. The results suggest that the amount of GH present between peaks might control cytochrome P450 output.
To test that hypothesis, the team infused young male rats with enough GH to slightly raise the amount of hormone present between spikes. After 4 days of treatment, the assortment of activated cytochrome P450s in the liver resembled that observed in old rats: Male-specific P450s waned, and female P450s waxed. The results suggest that the general decline in GH with age does not alter enzyme production; "it's the pattern of secretion" that influences physiology, says Shapiro.
The study shows that "elevation of the baseline" is the crucial factor in determining the pattern of cytochrome P450 activation, says molecular biologist David Waxman of Boston University. Whether the results will apply to people is unclear. Most studies suggest that humans don't exhibit the same gender or age variation in cytochrome P450 profiles that rats do, says Peter Syapin, a pharmacologist at Texas Tech University Health Sciences Center in Lubbock. Nevertheless, recent research reveals "a couple of hints" of such differences, suggesting that they "could be more important than we think," Syapin says. Further hunting might help researchers understand differences in how the elderly tolerate drugs and devise less trying ways to treat the ailments of aging.
--R. John Davenport
December 3, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150