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. 2010 Apr;77(4):575–592. doi: 10.1124/mol.109.061259

Fig. 13.

Fig. 13.

Heme-mediated translational control of PB-mediated CYP2B induction via hepatic HRI. A, heme-repleted, C57BL/6J mouse HRI-WT hepatocytes. PB-mediated activation of cytoplasmic constitutive androstane receptor (CAR) results in its translocation into the nucleus, where it heterodimerizes with another nuclear receptor, retinoid X receptor (RXR). The CAR-RXR heterodimeric complex then interacts with the PB-responsive enhancer module (PBREM) in the 5′-promoter region of CYP2B genes, thereby inducing their expression through enhanced transcriptional-translational activation as detailed (Kim et al., 2001; Williams et al., 2004; Timsit and Negishi, 2007). PB induction of CYP2B protein requires coordinated induction of heme synthesis. Under conditions of normal hepatic heme availability, hepatic HRI is inhibited and functionally inactive, and CYP2B protein translation proceeds normally. After all available hepatic heme is consumed, the ensuing transient heme depletion would activate HRI, in turn shutting off CYP2B protein translation. B, heme-deficient, C57BL/6J mouse HRI-WT hepatocytes. Similar PB-mediated CAR-RXR transcriptional activation of CYP2B genes via PBREM occurs in the heme-deficient liver. In concurrence with previous reports (Srivastava et al., 1989; Sinclair et al., 1990; Jover et al., 2000), heme deficiency does not affect the transcriptional activation of CYP2B genes (Fig. 10B; Han et al., 2005b). However, heme deficiency relieves hepatic HRI from inhibition, resulting in its autoactivation (via autophosphorylation), thereby unleashing its eIF2α kinase activity with consequent arrest of global hepatic protein translation, including that of CYP2B enzymes. C, heme-deficient, HRI KO (−/−) mouse hepatocytes. Genetic deletion of HRI results in the loss of this translational control in response to heme deficiency. Consequently, after PB induction, uncontrolled de novo synthesis of hepatic proteins, including CYP2B, proceeds undeterred despite insufficient heme for holoP450 assembly. Inordinate accumulation of hepatic protein triggers enhanced ubiquitination and an ER stress response as discussed.