This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Heme plays an important role in many cellular processes and dysregulation of its synthesis contributes to multiple diseases. Cellular heme homeostasis is regulated by multiple mechanisms that have typically been attributed to a combination of synthesis and degradation. Our recent findings extend this paradigm to reveal that a mitochondrial ABC transporter, Abcb6, regulates heme/porphyrin biosynthesis. A large proportion of heme usage in the liver is accounted for by cytochrome P450 isoforms, many of which are associated with drug metabolism. Each P450 is composed of a heme and an apoprotein moiety, whose cellular synthesis are tightly coordinated. Similar tight coordination of synthesis is also observed with other hemoproteins such as cytochrome c oxidase subunits of the mitochondrial respiratory chain, catalase and liver tryptophan 2,3-dioxygenase (TDO). In most of these cases, heme has been established as a transcriptional and translational activator of these hemoproteins. The modification of the enzymatic activity of the cytochrome P450 (CYP) enzymes by inhibition, induction, or activation is of great interest due to the potential of these alterations to greatly change the metabolism of the drug substrate for that enzyme and thereby alter the biological activity of the drug leading to the potential for harmful drug-drug interactions. Indeed P450 activity is impaired in several disorders of heme synthesis, such as in acute porphyrias and in acquired heme synthesis, such as in lead poisoning. Based on these observations we hypothesize that overexpression or interference with Abcb6 function might regulate hepatic CYP450 expression and/or function. Knowledge regarding the impact of Abcb6 on CYP450 activity has both immediate implications on the metabolism and disposition of pharmacological agents and environmental toxins and long term implications on drug clearance and drug toxicity.
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