Background to CYP7B1

• Enzyme activities hydroxylating sterols and steroids on the B ring (6 and 7 positions) were first described biochemically in diverse species; 7-hydroxylation of sterols and steroids is a primordial reaction [1]
• Cyp7b1 was first identified by Stapelton in mouse as a transcript selectively expressed in the hippocampus [2]
• The enzyme encoded by mammalian CYP7B1 hydroxylates DHEA, related steroids, and sterols including cholesterol, predominantly at the 7alpha position [3]
• High-level expression in hippocampus, liver, and other tissues was confirmed by transgenic knock-in [4] and by analysis of human brain tissue [5]
• Insight into the biological relevance of the Cyp7b1 reaction is provided by the rotational symmetry between substitutions at the 7alpha and 11beta positions and overlap between sterol and steroid (glucocorticoid) signaling [6]

Disease relevance of CYP7B1

• Mutation in CYP7B1 caused neonatal cholestasis [7].
• The present study reports effects of androgens and estrogens on human CYP7B1 transcription in prostate cancer LNCaP cells [8].
• We propose that CYP7B1 is important for regulating cellular sterol content and protects against oxysterol-mediated toxicity [9].
• SREBP suppressed a human CYP7B1 luciferase reporter gene in several cell lines, most markedly in rat hepatoma McA-RH7777 cells [9].

High impact information on CYP7B1

• CYP7B1 and CYP39A1 had no activity toward 4 beta-hydroxycholesterol [10].
• Hepatic CYP7A1 and CYP7B1 mRNA levels increased several-fold with age [11].
• Hepatic microsomal 7alpha-hydroxylation of 27-hydroxycholesterol and dehydroepiandrosterone, substrates typical for CYP7B1, increased about 5-fold between infancy and adolescence whereas the activities in kidney microsomes decreased at least 10-fold [11].
• Transient transfection assays of CYP7B1 promoter/luciferase reporter constructs in HepG2 cells revealed that the promoter was highly active [12].
• In contrast to the liver-specific expression of CYP7A1, CYP7B1 mRNA transcripts were detected in human tissues involved in steroid genesis (brain, testes, ovary, and prostate) and in bile acid synthesis (liver) and reabsorption (colon, kidney, and small intestine) [12].

Chemical compound and disease context of CYP7B1

• Regulation of steroid hydroxylase CYP7B1 by androgens and estrogens in prostate cancer LNCaP cells [8].
• The current study showed strong suppression of a human CYP7B1 luciferase reporter gene by dihydrotestosterone (DHT) in prostate cancer LNCaP cells [8].

Biological context of CYP7B1

• However, CYP7B1 spans at least 65 kb of the genome and is about 6-fold longer than CYP7A1 [12].
• The human CYP7A1 and CYP7B1 both contain six exons and five introns [12].
• Regulation by estrogens may also be of importance in other processes where CYP7B1 is involved, including cholesterol homeostasis, cellular proliferation, and CNS function [13].
• Since CYP7B1 diverts DHEA from the sex hormone biosynthetic pathway, estrogen receptor-mediated up-regulation of CYP7B1 should lead to less DHEA available for sex hormone synthesis and may help to maintain normal levels of estrogens and androgens in human tissues, especially during fetal development [13].
• Transient transfection assays of deletion mutants of the CYP7B1 promoter-luciferase reporter gene in human liver-derived HepG2, fibroblast NT1088, and human embryonic kidney 293 cell lines revealed that the region from -291 to +189 was critical for gene transcription [7].

Anatomical context of CYP7B1

• Quantitation of CYP7B1 mRNA in adult and fetal human tissues showed markedly higher CYP7B1 mRNA levels in fetal tissues compared with the corresponding adult ones, except in the liver [13].

Associations of CYP7B1 with chemical compounds

• The cloned human oxysterol 7alpha-hydroxylase (CYP7B1) cDNA encodes a polypeptide of 506 amino acid residues that shares 40% sequence identity to human cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver [12].
• The current study examines regulation of CYP7B1, a DHEA 7alpha-hydroxylase, by sex hormones [13].
• In the absence of receptors, 17beta-estradiol suppressed CYP7B1 activity, suggesting that estrogenic effects may be different in cells not expressing receptors [13].
• The 7alpha-hydroxy-DHEA produced by the cytochrome CYP7B1 in tissues may exert anti-glucocorticoid effects through interference with the 11beta-HSD1-mediated cortisone reduction [14].
• CYP7B1 was stimulated by synthetic ER agonists but suppressed by 17beta-estradiol and 5alpha-androstane-3beta,17beta-diol in LNCaP cells [8].

Other interactions of CYP7B1

• The mRNA levels of CYP8B1, CYP27A1, and CYP7B1 were not significantly altered in the treated groups [15].
• Hepatic CYP39A1 expression is sexually dimorphic (female > male), which is opposite that of CYP7B1 (male > female) [16].
• To examine the regulatory mechanisms governing CYP7B1 expression, the 5' flanking sequence of the CYP7B1 was analyzed and revealed a CpG island of about 1.2 kb [7].
• Our findings indicate that CYP7B1 transcription is controlled by SREBP and reveal a link between oxysterol-sensitive regulators and oxysterol metabolism [9].
• An SREBP-1-responsive region was mapped to a GC-rich sequence in the proximal CYP7B1 promoter, containing binding sites for the basal transcriptional activator Sp1 [9].

Analytical, diagnostic and therapeutic context of CYP7B1

• Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS [17].

References