Heme biosynthesis and drug metabolism in mice with hereditary hemolytic anemia. Heme oxygenase induction as an adaptive response for maintaining cytochrome P-450 in chronic hemolysis.

Abstract

Mice homozygous for the nb (normoblastosis) gene have severe hemolytic anemia characterized by in- creased catabolism of hemoglobin. Heme biosynthesis and catabolism were measured in the tissues of homo- zygous (nb/nb), heterozygous (+/nb), and control (+ / +) mice generated on the same genetic background. The functional capacity of the microsomal hemepro- tein, cytochrome P-450, was also determined in the livers of these animals. Mice homozygous for the nb gene defect had a marked increase in protoporphyrin content, S-aminolevulinic acid (ALA)-dehydratase, and uroporphyrinogen I (URO)-synthase activities in erythrocytes. Lesser in- creases were observed in liver and spleen of nb/nb mice. The homozygous mice also had a marked increase in microsomal heme oxygenase activity in the liver, kidney, and spleen compared to normal controls. The increase in heme oxygenase activity is attributable to a higher specific activity per mg of microsomal protein in the case of the liver and the kidney and to the marked organomegaly in the case of the spleen. Mice heterozygous for nb (+/nb) which do not have the overt hemolytic syndrome had normal levels of heme oxygenase activity, but elevated levels of ALA- dehydratase, URO-synthase, and protoporphyrin in blood. The increases observed in these indices in the heterozygotes were of a lesser magnitude than those observed with the nb/nb mice. The seemingly normal blood picture of the heterozygotes, therefore, probably reflects a compensated hemolytic state, as ALA-dehy- dratase, URO-synthase, and protoporphyrin levels are known to be increased in younger red cells. These enzymes and protoporphyrin were marginally increased in the liver, kidney, and spleen of the +/nb mice; heme oxygenase activity in these tissues was not altered. Both the homozygotes (nb/nb) with extensive hemolytic anemia and the heterozygotes (+/nb) with- out overt hemolysis had normal levels of microsomal cytochrome P-450 and no impairment of ethylmorphine N-demethylase or benzo(a)pyrene hydroxylase activi- ties in the liver. Cytochrome P-450 in the whole liver of * This work was supported in part by grants from the United States Public Health Service (ES-01055), the American Cancer Society (BC- 180A), the National Institutes of Health (CA-01074 and HD-00254), and the Energy Research and Development Administration (E-3264). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked