Hepatic heme metabolism in rats with fever induced by interleukin 1beta.

We have recently reported that the content of hepatic cytochrome P450 (CYP) apparently decreased in fever model rats, which were created by repeated injection of recombinant human interleukin-1beta (rhIL-1beta) into the cerebroventricle. To make clear the biochemical mechanism of the decreased CYP content, we examined the effect of fever on the activities of hepatic enzymes involved in the biosynthetic and degradative pathways of heme. The activities of delta-aminolevulinic acid synthase, a rate-limiting enzyme in the heme biosynthesis, and porphobilinogen synthase in the liver of rhIL-1beta-induced fevered rat were significantly lower than those in the control, whereas the activity of heme oxygenase, a key enzyme in the heme-degradative pathway, markedly increased in the fevered rat. Moreover, the heme saturation of tryptophan 2,3-dioxygenase in the fevered rat liver was decreased to 43% of the control. These results indicate that fever diminishes the hepatic heme content by decreasing the heme biosynthesis and by accelerating the heme degradation. The deficiency of hepatic heme pool may be one of the main mechanisms that cause the impairment of CYP synthesis.