Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal

Abstract

Heme is vital to our aerobic universe. Heme cellular content is finely tuned through an exquisite control of synthesis and degradation. Heme deficiency is deleterious to cells, whereas excess heme is toxic. Most of the cellular heme serves as the prosthetic moiety of functionally diverse hemoproteins, including cytochromes P450 (P450s). In the liver, P450s are its major consumers with >50% of hepatic heme committed to their synthesis. Prosthetic heme is the sine qua non of P450 catalytic biotransformation of both endo-and xenobiotics. This well-recognized functional role notwithstanding, heme also regulates P450 protein synthesis, assembly, repair and disposal. These less well-appreciated aspects are reviewed herein.

Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450

“…This is in agreement with many observations, according to which the addition of heme in hepatocyte cultures inhibits the drug-induced synthesis of ALAS 29–33 . Although xenobiotics might have some primary inducing effect on hepatic ALAS1, 34,35 many chemical inducers are believed to increase ALAS1 by depleting the free heme pool in hepatocytes 10 . This is in agreement with our observation in wild-type mice in which ALAS1 expression, CYP activity, and microsomal heme are increased, and cytosolic heme levels are reduced after drug treatment.…”

“…The free heme pool controls heme biosynthesis, through the regulation of ALAS1. If increased, the regulatory heme pool may repress ALAS1, 7 and its depletion causes ALAS1 induction 10 . Our results indicate that ALAS1 induction occurs in wild-type as well as in Flvcr1a -null mice shortly after cytochrome stimulation, to sustain heme synthesis for cytochrome formation.…”

“…The cytosolic heme fraction contains a pool of newly synthesized heme that serves both precursor and regulatory functions 10 . The free heme pool controls heme biosynthesis, through the regulation of ALAS1.…”

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

“…Traditional methods to probe heme bioavailability involve assaying the activities of various heme-dependent enzymes and transcription factors in cell or tissue extracts, including cytochrome P 450 enzymes (ER) [239,240], catalase (peroxisomes or mitochondria) [92,241], tryptophan 2,3 dioxygenase (cytosol) [242], indoleamine-2,3-dioxygenase (cytosol) [243], various nuclear transcription factors, e.g., Hap1 (in yeast), Bach1, p53 and Reverb-α/β [2,3,92,241] and peroxidases that can be genetically encoded and targeted to different subcellular compartments [174,244] (Table 2). While these methods have shed considerable insight into heme homeostatic mechanisms, they suffer from a number of drawbacks that arise from harsh lysis conditions and time-intensive enzyme assays.…”

Mitochondrial Heme Synthesis Enzymes as Therapeutic Targets in Vascular Diseases

“…Similarly, different forms of heme are incorporated into mitochondrial respiratory complexes I-IV of the electron transport chain (ETC) (Kim et al, 2012). Of course, the majority of heme is used for incorporation into hemoglobin during erythropoiesis (Korolnek and Hamza, 2014) and some (primarily in the liver) for the synthesis of cytochrome P450s, responsible for xenobiotic metabolism (Correia et al, 2011).…”