Differences in the metabolic response to exogenous homocysteine in juvenile and adult rabbits

Homocysteine has recently received a lot of attention as an independent risk factor for atherosclerotic and thrombotic cardiovascular disease. Plasma homocysteine levels tend to rise with age, but are also greatly influenced by nutritional factors. Early reports suggested that there were differences in the metabolism of homocysteine in adult and immature animals. The current work tests the hypothesis that adult and juvenile animals respond differently to chronic administration of homocysteine. We have previously found that adult rabbits given homocysteine parenterally twice daily for seven weeks developed progressive folate deficiency and concurrently developed an impairment of homocysteine metabolism. We now report that juvenile rabbits do not develop folate deficiency with chronic homocysteine loading and do not have progressively higher trough levels of homocysteine, as do the adults. In addition, juvenile rabbits that have been chronically pre-treated with homocysteine exhibit a lower peak homocysteine level after a single dose than do juvenile rabbits that have never received homocysteine. This adaptation did not occur in the adult rabbits. In addition, adult homocysteine-treated rabbits had evidence of oxidative stress as evidenced by higher levels of malondialdehyde in liver tissue than adult controls. The homocysteine-treated juvenile rabbits had the same levels of malondialdehyde as the juvenile control rabbits. We conclude that the plasma elimination kinetics are altered in juvenile rabbits in response to homocysteine pre-treatment. The difference in metabolism of homocysteine may protect the juvenile rabbits from the damaging effects of homocysteine. Future studies are planned to elucidate the mechanism of this adaptive response.