A Novel Cytochrome P450 Expressed Primarily in Brain

Abstract

hct-1 (hippocampal transcript) was detected in a differential screen of a rat hippocampal cDNA library. Expression of hct-1 was enriched in the formation but was also detected in rat liver and kidney, though at much lower levels; expression was barely detectable in testis, ovary, and adrenal. In liver, unlike brain, expression was sexually dimorphic; hepatic expression was greatly reduced in female rats. In mouse, brain expression was widespread, with the highest levels being detected in corpus callosum; only low levels were detected in liver. Sequence analysis of rat and mouse hct-1 cDNAs revealed extensive homologies with cytochrome P450s (CYPs), a diverse family of heme-binding monooxygenases that metabolize a range of substrates including steroids, fatty acids, and xenobiotics. Among the CYPs, hct-1 is most similar (39% at the amino acid sequence) to cholesterol 7␣-hydroxylase (CYP7) and contains a postulated steroidogenic domain present in other steroidmetabolizing CYPs but clearly represents a type of CYP not previously reported. Genomic Southern analysis suggests that a single gene corresponding to hct-1 is present in mouse, rat, and human. hct-1 is unusual in that, unlike all other CYPs described, the primary site of expression is in the brain. Similarity to CYP7 and other steroid-metabolizing CYPs may argue that hct-1 (CYP7B) plays a role in steroid metabolism in brain, notable because of the documented ability of brain-derived steroids (neurosteroids) to modulate cognitive function in vivo.Cytochromes P450, a diverse group of heme-containing monooxygenases (termed CYPs) 1 (for nomenclature see Nelson et al. (1)), catalyze a variety of oxidative conversions, notably of steroids but also of fatty acids and xenobiotics. Though most abundantly expressed in the testis, ovary, placenta, adrenal, and liver, the brain is a further site of CYP expression (2-6).Several CYP activities or mRNAs have been reported in the nervous system, predominantly of types metabolizing fatty acids and xenobiotics (subclasses CYP2C, -2D, -2E, and -4 (6, 7)). However, primary rat brain-derived glial cells can synthesize pregnenolone and progesterone in vitro (8). Mellon and Deschepper (9) provided molecular evidence for the presence, in brain, of key steroidogenic enzymes CYP11A1 (scc) and CYP11B1 (11␤) but failed to detect CYP17 (c17) or CYP11B2 (AS). Though CYP21A1 (c21) activity is reported to be present in brain (10) authentic CYP21A1 transcripts were not detected (11).Interest in brain steroid metabolism has been fueled by the finding that adrenal-and brain-derived steroids (neurosteroids) can modulate cognitive function and synaptic plasticity (reviewed in Refs. 12-17). For instance, pregnenolone and steroids derived from it are reported to have memory-enhancing effects in mice (18,19). However, the full spectrum of brain CYPs and the biological roles of their metabolites in vivo have not been established.To investigate such regulation of brain function our studies have focused on the hippocampus, a brain region important ...

Endogenous Synthesis of Corticosteroids in the Hippocampus

“…Several unknown peaks are also observed in the metabolism analysis. These unknown products may be 7-hydroxylated steroids (such as 7α-OH PROG) or 20-hydroxylated steroids, because the expression of Cyp7b and 20α-hydroxylase in the rodent hippocampus are reported [44], [45]. (B) Typical HPLC profiles of 3 H-DOC metabolites.…”

7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

“…Although CYP 7A1 is generally considered to be a liver-specific enzyme [40], there are no published reports to date that demonstrate directly either the presence or the absence of this enzymatic activity in the retina. However, CYP 7B1, an oxysterol and steroid 7α-hydroxylase, is abundant in the nervous system (although, again, neither directly demonstrated to be present in or absent from retina) [41, 42]. Thus, the possibility remains that either CYP 7A1 or 7B1 or both may be responsible, in part, for the conversion of 7-DHC to 7-kChol in the mammalian retina.…”

The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol

“…27HC is metabolized by another P450 enzyme, oxysterol 7α-hydroxylase (CYP7B1). CYP7B1 is expressed in the brain, particularly in the hippocampus, but is also expressed in liver and other peripheral organs [20,21]. Although the physiological concentration of these substrates should be considered, CYP7B1 has a relatively broad substrate specificity for steroids and sterols such as dehydroepiandrosterone (DHEA), 5α-androstane-3β, 17β-diol (3Adiol), 25-hydroxycholesterol, pregnenorone, 17β-estradiol (E 2 ) and 27HC, as a 7α-hydroxylase [21–23].…”