Regulation of hepatic CYP2B enzymes: Translational control via the heme‐regulated inhibitor (HRI)

Phenobarbital (PB)‐induction of hepatic CYP2B synthesis entails a well‐characterized constitutive androstane receptor‐mediated transcription/translation process. Our objective was to show that heme could regulate PB‐mediated‐induction of hepatic CYP2B synthesis at the translational level, most likely via the hepatic heme‐regulated inhibitor (HRI). We have shown that hepatic HRI exists in mice, rats and humans and functions as a heme‐sensitive eIF2α (eukaryotic translation initiation factor) kinase. Acute heme depletion of rat or mouse hepatocytes results in activation of HRI via autophosphorylation. Once activated, it phosphorylates eIF2α which in turn results in global translational arrest of hepatic proteins including that of CYP2B enzymes. Heme repletion reverses these effects. To further document a direct role for HRI in translational control of hepatic CYP2B enzymes, we have used a HRI (−/−) knockout (KO) mouse model. Acute heme depletion of KO‐mouse hepatocytes results in constitutive heme‐insensitive PB or Dexamethasone‐mediated induction of CYP2B and CYP3A enzymes respectively, unlike in the corresponding wild type [WT; HRI (+/+)].Thus HRI is a key heme‐sensitive translational regulator of hepatic P450 syntheses. Additionally we found that HRI content and phosphorylation is increased by P450 inducers such as PB, rifampin and barbituric acid. Collectively, our findings indicate that HRI activation after acute hepatic heme depletion in genetically predisposed individuals can result in global translational shut‐off of physiologically critical proteins leading to the severe and often fatal clinical symptomatology of acute hepatic porphyrias the severity of which could be further exacerbated upon HRI induction by cytochrome P450 inducers. Supported by NIH grants DK26506 and DK26743.