Effects of Cytochrome P450 Inducers on the Gene Expression of Ocular Xenobiotic Metabolizing Enzymes in Rats

In our current study, we investigated the expression profiles of the cytochromes P450 (CYPs) and transporters of the ocular tissues in Sprague-Dawley (SD) rats. Extensive expression of CYP1A1 in the cornea and CYP2E1 in the iris was observed whereas the expression of CYP2B1 and transporters was Mostly ubiquitous throughout the ocular tissues. To further understand the regulation of these genes in ocular tissues, we investigated the effects of CYP inducers on the expression of the CYP and other xenobiotic-metabolizing enzyme genes in the cornea and lens. The administration of P-naphthoflavone (BNF), an agonist for aryl hydrocarbon receptor (AhR), induced CYP1A1 gene expression in the cornea, lens and liver of the rats, although the levels of induction were greatest in the liver. An AhR-sensitive UDP-glucuronosyl transferase (UGT) 1A6 gene was also induced in the cornea and the lens by BNF. Phenobarbital (PB) is a known inducer of the CYP2B genes, the expression of which is mediated by constitutive activated receptor (CAR), but did not induce CYP2B1 in the cornea or lens. This insensitivity to PB may be due to the lack of CAR expression in the ocular tissues as revealed in our present study. Pregnenolone-16 alpha-carbonitrile (PCN) is known to induce CYP3A gene expression in the liver via the activation of pregnane X receptor (PXR). However, although PCN was found to induce the CYP3A1 gene in the rat cornea and liver, it failed to do so in the lens. In addition, another of the PXR-mediated genes, multidrug resistance-associated protein 3 (Mrp3), was not induced by PCN in either ocular region. Since the expression of the PXR gene was not detected in the rat ocular tissues, an unknown mechanism for the inducible regulation of CYP3A1 gene expression by PCN in the cornea is suggested.