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Xenobiotic nuclear receptors (NR) are intracellular players involved in an increasing number of physiological processes. Examined and characterized in peripheral organs where they govern metabolic, transport and detoxification mechanisms, accumulating data suggest a functional expression of specific NR at the neurovascular unit (NVU). Here, we focus on the Constitutive Androstane Receptor (CAR), expressed in detoxifying organs such as the liver, intestines and kidneys. By direct and indirect activation, CAR is implicated in hepatic detoxification of xenobiotics, environmental contaminants, and endogenous molecules (bilirubin, bile acids). Importantly, CAR participates in physiological stress adaptation responses, hormonal and energy homeostasis due to glucose and lipid sensing. We next analyze the emerging evidence supporting a role of CAR in NVU cells including the blood–brain barrier (BBB), a key vascular interface regulating communications between the brain and the periphery. We address the emerging concept of how CAR may regulate specific P450 cytochromes at the NVU and the associated relevance to brain diseases. A clear understanding of how CAR engages during pathological conditions could enable new mechanistic, and perhaps pharmacological, entry-points within a peripheral–brain axis.

BACKGROUND: We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro. OBJECTIVE: Our purpose was (i) to identify the molecular mechanism involved and (ii) to characterize the inducer compound(s) in serum involved at least in part. METHODS: Serum was fractionated on hydrophobic columns. PPARα involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS. RESULTS: The inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARα cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARα, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities. CONCLUSION: We demonstrate that serum induces CYP1A1 via the PPARα pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARα.