Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency.
Previous work has demonstrated that the function of extrahepatic cytochrome P450 CYP1A1 is dependent on the availability of heme. CYP1A1 is involved in the activation of polyaromatic hydrocarbons. In the present study we used a transgenic mouse model with chronic impairment of heme synthesis - female porphobilinogen deaminase-deficient (PBGD-/-) mice - to investigate the effects of limited heme in untreated and beta-naphthoflavone (beta-NF)-treated animals on the function of CYP1A1 in brain. The heme content of PBGD-/- mice was diminished in the liver and brain compared to wild types. In the liver, partial heme deficiency led to less potent induction of CYP1A1 mRNA after beta-NF treatment. In the brain, CYP1A1 protein was detected not only at the endoplasmic reticulum (ER), but also in the cytosol of PBGD-/- mice. Furthermore, 7-deethylation of ethoxyresorufin, an indicator of CYP1A1 metabolic activity, could be restored by heme in cytosol of PBGD-/- mouse brain. Independent of the genotype, we found only one cyp1a1 gene product, indicating that the cytosolic appearance of CYP1A1 most likely did not originate from mutant alleles. We conclude that heme deficiency in the brain leads to incomplete heme saturation of CYP1A1, which causes its improper incorporation into the ER membrane and persistence in the cytosol. It is suggested that diseases caused by relative heme deficiency, such as hepatic porphyrias, may lead to impaired hemoprotein function in brain.
Meyer
Ralf P
RP
Department of Neuropathology, Neurozentrum, University of Freiburg, Breisacherstrasse 64, D-79106 Freiburg, Germany. ralf.meyer@uniklinik-freiburg.de
Lindberg
Raija L P
RL
Hoffmann
Francine
F
Meyer
Urs A
UA
D000818:Animals; D001921:Brain / Q000201:enzymology; D002908:Chronic Disease; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006418:Heme / Q000032:analysis / Q000172:deficiency*; D011163:Hydroxymethylbilane Synthase / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D013347:Subcellular Fractions / Q000201:enzymology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D006418:Heme; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D011163:Hydroxymethylbilane Synthase