Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Abstract

Cytochrome P450 (P450) enzymes play a critical role in the activation and detoxication of many neurotoxic chemicals. Although research has largely focused on P450-mediated metabolism in the liver, emerging evidence suggests that brain P450s influence neurotoxicity by modulating local metabolite levels. As a first step toward better understanding the relative role of brain P450s in determining neurotoxic outcome, we characterized mRNA expression of specific P450 isoforms in the rodent brain. Adult mice (male and female) and rats (male) were treated with vehicle, phenobarbital, or dexamethasone. Transcripts for CYP2B, CYP3A, CYP1A2, and the orphan CYP4X1 and CYP2S1 were quantified in the liver, hippocampus, cortex, and cerebellum by quantitative (real-time) polymerase chain reaction. These P450s were all detected in the liver with the exception of CYP4X1, which was detected in rat but not mouse liver. P450 expression profiles in the brain varied regionally. With the exception of the hippocampus, there were no sex differences in regional brain P450 expression profiles in mice; however, there were marked species differences. In the liver, phenobarbital induced CYP2B expression in both species. Dexamethasone induced hepatic CYP2B and CYP3A in mice but not rats. In contrast, brain P450s did not respond to these classic hepatic P450 inducers. Our findings demonstrate that P450 mRNA expression in the brain varies by region, regional brain P450 profiles vary between species, and their induction varies from that of hepatic P450s. These novel data will be useful for designing mechanistic studies to examine the relative role of P450-mediated brain metabolism in neurotoxicity. IntroductionThe cytochrome P450 (P450) superfamily is a diverse group of enzymes that catalyze the oxidative metabolism of not only endogenous substrates but also xenobiotics, including environmental contaminants of significant public health concern that target the nervous system, including polychlorinated biphenyls, polybrominated diphenyl ethers, and organophosphorus pesticides (Ariyoshi et al., 1995;Foxenberg et al., 2007;Erratico et al., 2013;Feo et al., 2013). Biotransformation of these compounds by P450s can result in bioactivation or detoxication, and the balance between these activities influences the bioeffective dose, and thus the neurotoxic outcome, following environmental exposures, as shown in studies of humans and animal models (Foxenberg et al., 2007;Curran et al., 2011;Kim et al., 2011;Crane et al., 2012;Khokhar and Tyndale, 2012).Much of the research effort to characterize P450-mediated metabolism of neurotoxic compounds has focused on the liver. However, it is now evident that P450s are expressed in a number of extrahepatic tissues, including brain (Ding and Kaminsky, 2003;Ferguson and Tyndale, 2011). Although total P450 content in the human and rodent brain is generally significantly lower than that in the liver (Warner et al., 1988;Bhamre et al., 1992;Volk et al., 1995), recent evidence from rat studies demonstrates that P45...

Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice

“…The mechanistic basis for the sex difference in the extent of PB-induced hepatocyte proliferation and the apparent noninvolvement of CYP2B in the proliferative response in females are currently not understood, but they may be partly explained by the lower extent of hepatic CYP2B induction by PB in females than in males. In that regard, our present result was consistent with previous reports, that PB induced CYP2B10 to a larger extent in males than in females (Li-Masters and Morgan, 2001;Stamou et al, 2014) and that male mice were more susceptible to PB-induced hepatocarcinogenesis than female mice (Heindryckx et al, 2009;Maronpot, 2009). This sex difference in CYP2B inducibility by PB does not appear to be due to a difference in CAR expression, because cytosolic (Hernandez et al, 2009) or nuclear (Saito et al, 2013) CAR protein level was found to be similar between untreated male and female mice.…”

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

“…3). In some brain regions, such as the cortex, hippocampus, striatum, and thalamus, PB and 2,4,6-tryphenyl dioxane did not affect CYP2B expression; in contrast, these agents caused a dramatic increase in CYP2B expression in the liver (Upadhya et al, 2002;Pustylnyak et al, 2009;Stamou et al, 2014). These results suggested that another mechanism, not involving CAR, may have contributed to the transcriptional activation of Ugt1a6 and Ugt1a7 in the rat brain.…”

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

“…A northern blot analysis demonstrated that CYP4X1 mRNA is strongly and specifically expressed in the rat brain stem, hippocampus, and vascular endothelial cells (Bylund et al, 2002). Stamou et al (2013) previously reported that CYP4X1 mRNA is equally detectable in the rat liver and brain. Al-Anizy et al (2006) showed the selective expression of Cyp4x1 in the mouse brain, while CYP4X1 mRNA was ubiquitously expressed in adult human tissues (Choudhary et al, 2005).…”

“…The characterization of brain and/or neural CYP enzymes and their localization as well as the identification of endogenous substrates and their metabolic endproducts will provide a better understanding of the role of CYP enzymes in brain physiology, development, and diseases (Ghosh et al, 2016;Toselli et al, 2016). It may also be qualitatively and quantitatively different from that in the liver due to differences in expression or to the presence of unique enzymes in the brain and particular neurons (Stamou et al, 2013). Furthermore, useful cell lines for drug metabolism studies in the brain have not yet been established.…”