Regional Distribution of Cytochrome P‐450 in the Rat Brain: Spectral Quantitation and Contribution of P‐450b,e and P‐450c,d

Abstract

The cytochrome P-450 (P-450) content of different regions of the rat brain was measured after partial purification of the enzyme from homogenates, and the quantitative contribution of P-450b,e and P-450c,d to brain P-450 was assessed by Western immunoblotting and immunohistochemistry using rabbit antibodies raised against purified hepatic P-450b and P-450c, respectively). P-450 could be quantitated by its reduced CO difference spectrum after chromatography of homogenates on p-chloroamphetamine-coupled Sepharose. The yield of P-450 from whole brain was 90 +/- 19 pmol/g of tissue, which is approximately 1% of the level in liver microsomes from control rats. The amount of P-450 recovered from homogenates of olfactory lobes, hypothalamus, thalamus, striatum, cerebral cortex, and brainstem varied between 40 and 100 pmol/g of tissue. The cerebellum was a region of exceptionally high P-450 content, with yields of up to 400 pmol/g whereas the substantia nigra yielded only 16-20 pmol/g. Immunohistochemical studies with anti-P-450b and anti-P-450c revealed intense staining of a limited number of cells in the cerebellum with both antibodies and in the thalamus only with anti-P-450c. In the cerebellum, both anti-P-450b and anti-P-450c stained the Bergmann glial cells together with their radial processes. Individual glial cells in the granular cell layer were also stained. There was no staining of Purkinje cells. In the thalamus, anti-P-450b gave weak staining of certain astroglia, but with anti-P-450c, there was intense staining of neuronal somata.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo steady‐state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats

“…The parenchyma volume may also vary, but more importantly the lipophilicity may vary between the brain regions, and thus, result in di erent drug concentrations between the brain regions. It should also be noted, that the expression of the CYP-enzymes are present in the brain as well as in the liver (Ravindranath et al, 1995;Voirol et al, 2000;Warner et al, 1988).…”

Cytochrome P450–mediated drug metabolism in the brain

“…Early investigations estimated that CYPs are expressed at levels almost 100 times lower in the brain than in the liver, 38 and it was difficult to conceive how these brain CYPs could have any functional consequences. However, as CYP protein expression was mapped across brain regions and cell types, it became evident that their expression levels vary greatly among specific brain regions and that, at the cellular level, expression can be as high as levels in hepatocytes.…”

“…During the next decade, researchers continued to quantify brain CYPs and to assess their metabolic activity toward different substrates. [33][34][35][36][37][38] Most brain CYPs metabolize substrates with similar affinities, and relative substrate and inhibitor selectivity, to their hepatic counterparts. However, there are CYP forms that are unique to the brain or that are much more highly expressed in brain than in other tissues, including CYP2D4 and CYP2D18 [39][40][41] and some members of the CYP3A families in rats.…”

The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline‐preferring receptors

“…The rat brain also expresses these enzymes (Warner et al, 1988;Bergh et al, 1992) and a significant proportion are located on mitochondria (Walther et al, 1986). Thus, the possibility that 12 imidazoline-preferring receptors could be a form of these enzymes was investigated.…”