CYP7B1: One Cytochrome P450, Two Human Genetic Diseases, and Multiple Physiological Functions

The CYP7B1 cytochrome P450 enzyme hydroxylates carbons 6 and 7 of the B ring of oxysterols and steroids. Hydroxylation reduces the biological activity of these substrates and facilitates their conversion to end products that are readily excreted from the body. CYP7B1 is expressed in the liver, reproductive tract, and brain and performs different physiological functions in each tissue. Hepatic CYP7B1 activity is crucial for the inactivation of oxysterols and their subsequent conversion into bile salts. Loss of CYP7B1 activity is associated with liver failure in children. In the reproductive tract, the enzyme metabolizes androgens that antagonize estrogen action; mice without CYP7B1 have abnormal prostates and ovaries. The role of CYP7B1 in brain is under investigation; recent studies show that spastic paraplegia type 5, a progressive neuropathy, is caused by loss-of-function mutations in the human gene. The CYP7B1 cytochrome P450 enzyme hydroxylates carbons 6 and 7 of the B ring of oxysterols and steroids. Hydroxylation reduces the biological activity of these substrates and facilitates their conversion to end products that are readily excreted from the body. CYP7B1 is expressed in the liver, reproductive tract, and brain and performs different physiological functions in each tissue. Hepatic CYP7B1 activity is crucial for the inactivation of oxysterols and their subsequent conversion into bile salts. Loss of CYP7B1 activity is associated with liver failure in children. In the reproductive tract, the enzyme metabolizes androgens that antagonize estrogen action; mice without CYP7B1 have abnormal prostates and ovaries. The role of CYP7B1 in brain is under investigation; recent studies show that spastic paraplegia type 5, a progressive neuropathy, is caused by loss-of-function mutations in the human gene. There are two general types of cytochrome P450 enzymes, those that act on endogenous substrates like lipids and those whose primary function is to act on exogenous substrates like drugs and environmental chemicals. Deciding whether a new P450 acts on endogenous versus exogenous substrates is difficult in the absence of experimental analysis. This was the case for the P450 now known as CYP7B1, whose cDNA was initially isolated from a rat hippocampal library and described in the Journal of Biological Chemistry as a new P450 with 39% sequence identity to cholesterol 7α-hydroxylase (CYP7A1) (1Stapleton G. Steel M. Richardson M. Mason J.O. Rose K.A. Morris R.G. Lathe R. J. Biol. Chem. 1995; 270: 29739-29745Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). The latter enzyme acts on an endogenous substrate (cholesterol) and plays an important role in bile salt synthesis (2Russell D.W. Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1493) Google Scholar), but what role did CYP7B1 play? Subsequent biochemical experiments showed that CYP7B1 also acted on endogenous substrates, hydroxylating dehydroepiandrosterone, pregnenolone, and other steroids (3Rose K.A. Stapleton G. Dott K. Kieny M.P. Best R. Schwarz M. Russell D.W. Björkhem I. Seckl J. Lathe R. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 4925-4930Crossref PubMed Scopus (207) Google Scholar) as well as two oxysterols, 25-hydroxycholesterol (4Schwarz M. Lund E.G. Lathe R. Björkhem I. Russell D.W. J. Biol. Chem. 1997; 272: 23995-24001Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar) and 27-hydroxycholesterol (5Martin K.O. Reiss A.B. Lathe R. Javitt N.B. J. Lipid Res. 1997; 38: 1053-1058Abstract Full Text PDF PubMed Google Scholar). Here, we review the biochemistry, physiology, and genetics of CYP7B1, which reveal the enzyme to be a multifunctional P450. The CYP7B1 gene encodes an evolutionarily conserved P450 and is found in the genomes of organisms ranging from humans to the Japanese fire-bellied newt to the fungus Aspergillus niger. The human gene spans ∼220 kb on chromosome 8q21.3 and encompasses six exons separated by five introns (Fig. 1A). Transcription is initiated ∼200 bp 5′ of the initiation codon in exon 1 and produces an mRNA of ∼9 kb that has a long (∼7 kb) 3′-untranslated sequence (6Wu Z. Martin K.O. Javitt N.B. Chiang J.Y. J. Lipid Res. 1999; 40: 2195-2203Abstract Full Text Full Text PDF PubMed Google Scholar). The tissue-specific expression pattern of the CYP7B1 gene differs between species. The human mRNA is present in many organs, with the highest levels detected in kidney and brain (6Wu Z. Martin K.O. Javitt N.B. Chiang J.Y. J. Lipid Res. 1999; 40: 2195-2203Abstract Full Text Full Text PDF PubMed Google Scholar). The mRNA is also widely distributed among different rat tissues (7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Expression is restricted to the liver, lung, kidney, brain, and reproductive tract in the mouse, with the amount of mRNA being highest in liver and lung. 4J. Repa, personal communication. As with several other P450 enzymes, the CYP7B1 mRNA, protein, and enzyme activity in liver and kidney are higher in male mice than in female mice, and this sexually dimorphic expression requires androgen receptor signaling (8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). The biological significance of this male-female difference and whether a similar pattern of expression exists in other species are not known. The human mRNA encodes a 506-amino acid enzyme (EC 1.14.13.100) that catalyzes the 6α- or 7α-hydroxylation of several steroids and oxysterols (Fig. 1B). NADPH and cytochrome P450 oxidoreductase serve as cofactors in these reactions, and based on the latter requirement, CYP7B1 is presumed to be located in the endoplasmic reticulum. An anti-peptide antibody raised in a rabbit against amino acids 266–281 of mouse CYP7B1 recognizes a protein with an Mr of ∼58,000 on immunoblots (4Schwarz M. Lund E.G. Lathe R. Björkhem I. Russell D.W. J. Biol. Chem. 1997; 272: 23995-24001Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), which is in good agreement with that (Mr = 58,359) predicted from conceptual translation of the mouse cDNA. The enzyme has not been purified and kinetically characterized; thus, whether steroids are better substrates than oxysterols or whether preferences exist within these two classes remains to be determined. The properties of CYP7B1 isolated from different species may differ, as nafimidone (1-(2-naphthoylmethyl)imidazole) selectively inhibits the mouse but not the human enzyme (4Schwarz M. Lund E.G. Lathe R. Björkhem I. Russell D.W. J. Biol. Chem. 1997; 272: 23995-24001Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). The three-dimensional structure of CYP7B1 has yet to be solved, but a structure at 2.15 Å is available for cholesterol 7α-hydroxylase (CYP7A1, Protein Data Bank code 3DAX), which, as noted above, shares sequence identity and sterol substrate partiality with the enzyme. A major metabolic fate of cholesterol is conversion into conjugated bile salts in liver (2Russell D.W. Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1493) Google Scholar). Once synthesized, bile salts act in the intestine to facilitate solubilization of hydrophobic nutrients from the diet, including fat-soluble vitamins and cholesterol. In liver, bile salts stimulate bile flow and the excretion of metabolites such as porphyrins that arise from the breakdown of heme. The identification and cDNA cloning of the enzymes that participate in bile salt synthesis began in the late 1980s (9Russell D.W. J. Lipid Res. 2009; 50: S120-S125Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar), and inter alia, these studies showed that both cholesterol and oxysterols are substrates for bile salt synthesis. The first and rate-limiting step in the cholesterol pathway involved 7α-hydroxylation, a reaction catalyzed by cholesterol 7α-hydroxylase (10Danielsson H. Einarsson K. Johansson G. Eur. J. Biochem. 1967; 2: 44-49Crossref PubMed Scopus (191) Google Scholar). Björkhem and co-workers (11Toll A. Wikvall K. Sudjana-Sugiaman E. Kondo K.H. Björkhem I. Eur. J. Biochem. 1994; 224: 309-316Crossref PubMed Scopus (40) Google Scholar) later showed that a different enzyme was involved in 7α-hydroxylating oxysterols, and the finding that CYP7B1 shared sequence identity with cholesterol 7α-hydroxylase suggested that CYP7B1 might be an oxysterol 7α-hydroxylase. Genetic, pharmacological, and biochemical experiments subsequently confirmed this hypothesis (Table 1) (4Schwarz M. Lund E.G. Lathe R. Björkhem I. Russell D.W. J. Biol. Chem. 1997; 272: 23995-24001Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 12Schwarz M. Lund E.G. Setchell K.D. Kayden H.J. Zerwekh J.E. Björkhem I. Herz J. Russell D.W. J. Biol. Chem. 1996; 271: 18024-18031Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar).TABLE 1Physiological roles of CYP7B1Role/tissueSubstratesRefs.Bile salt synthesisLiver25-Hydroxycholesterol, 27-hydroxycholesterol8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 14Schwarz M. Russell D.W. Dietschy J.M. Turley S.D. J. Lipid Res. 2001; 42: 1594-1603Abstract Full Text Full Text PDF PubMed Google Scholar, 29Setchell K.D. Schwarz M. O'Connell N.C. Lund E.G. Davis D.L. Lathe R. Thompson H.R. Weslie Tyson R. Sokol R.J. Russell D.W. J. Clin. Invest. 1998; 102: 1690-1703Crossref PubMed Scopus (304) Google ScholarSteroid hormone metabolismBrainPregnenolone, dehydroepiandrosterone3Rose K.A. Stapleton G. Dott K. Kieny M.P. Best R. Schwarz M. Russell D.W. Björkhem I. Seckl J. Lathe R. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 4925-4930Crossref PubMed Scopus (207) Google Scholar, 7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google ScholarMetabolism of estrogen receptor ligandsProstate5α-Androstane-3β,17β-diol19Weihua Z. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 13589-13594Crossref PubMed Scopus (295) Google Scholar, 20Omoto Y. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 2814-2819Crossref PubMed Scopus (45) Google ScholarProstateDehydroepiandrosterone?23Martin C. Ross M. Chapman K.E. Andrew R. Bollina P. Seckl J.R. Habib F.K. J. Clin. Endocrinol. Metab. 2004; 89: 2928-2935Crossref PubMed Scopus (43) Google Scholar, 24Pettersson H. Holmberg L. Axelson M. Norlin M. FEBS J. 2008; 275: 1778-1789Crossref PubMed Scopus (31) Google ScholarVasculature27-Hydroxycholesterol21Umetani M. Domoto H. Gormley A.K. Yuhanna I.S. Cummins C.L. Javitt N.B. Korach K.S. Shaul P.W. Mangelsdorf D.J. Nat. Med. 2007; 13: 1185-1192Crossref PubMed Scopus (317) Google Scholar, 22DuSell C.D. Umetani M. Shaul P.W. Mangelsdorf D.J. McDonnell D.P. Mol. Endocrinol. 2008; 22: 65-77Crossref PubMed Scopus (226) Google ScholarImmunoglobulin productionImmune cells25-Hydroxycholesterol25Diczfalusy U. Olofsson K.E. Carlsson A.M. Gong M. Golenbock D.T. Rooyackers O. Fläring U. Björkbacka H. J. Lipid Res. 2009; 50 (in press)Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 26Bauman D.R. Bitmansour A.D. McDonald J.G. Thompson B.M. Russell D.W. Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (in press)Crossref PubMed Scopus (251) Google Scholar Open table in a new tab A majority of mice lacking cholesterol 7α-hydroxylase die from vitamin and caloric deficiencies in the first 18–21 days of life (13Ishibashi S. Schwarz M. Frykman P.K. Herz J. Russell D.W. J. Biol. Chem. 1996; 271: 18017-18023Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar); thereafter, the expression of CYP7B1 is induced in liver, resulting in the synthesis of bile salts and the prevention of further premature death (12Schwarz M. Lund E.G. Setchell K.D. Kayden H.J. Zerwekh J.E. Björkhem I. Herz J. Russell D.W. J. Biol. Chem. 1996; 271: 18024-18031Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). Adult cholesterol 7α-hydroxylase-deficient mice contain ∼30% of the normal amount of bile salts, suggesting that oxysterols are precursors for about one-third of the bile salt pool in this species (14Schwarz M. Russell D.W. Dietschy J.M. Turley S.D. J. Lipid Res. 2001; 42: 1594-1603Abstract Full Text Full Text PDF PubMed Google Scholar). Cholesterol balance studies support this estimate and indicate that cholesterol 7α-hydroxylase expression is ∼30% higher in CYP7B1 knock-out mice 5Two lines of CYP7B1 knock-out mice are described in the literature (7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). The phenotypes of these two lines are not always similar. Whether differences arise from genetic background, diet, infection, investigator error, or a combination of these variables has not been determined. References indicate the line of mice in which a particular observation was made. ; this increase in expression produces a normal bile salt pool (8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Both 25- and 27-hydroxycholesterol accumulate in the sera and tissues of CYP7B1 mutant mice (8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), a finding that supports their in vivo roles as enzyme substrates. Unexpectedly, the related side chain oxysterol, 24-hydroxycholesterol, does not accumulate; this sterol is metabolized to a bile salt precursor by another oxysterol 7α-hydroxylase, CYP39A1 (15Li-Hawkins J. Lund E.G. Bronson A.D. Russell D.W. J. Biol. Chem. 2000; 275: 16543-16549Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). CYP7B1 was initially identified as a steroid 7α-hydroxylase with activity toward pregnenolone, a 21-carbon steroid, and dehydroepiandrosterone, a 19-carbon steroid (3Rose K.A. Stapleton G. Dott K. Kieny M.P. Best R. Schwarz M. Russell D.W. Björkhem I. Seckl J. Lathe R. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 4925-4930Crossref PubMed Scopus (207) Google Scholar). This result, the isolation of the cDNA from a hippocampal library (1Stapleton G. Steel M. Richardson M. Mason J.O. Rose K.A. Morris R.G. Lathe R. J. Biol. Chem. 1995; 270: 29739-29745Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), and histochemical data (7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) suggested that CYP7B1 had a function in brain (Table 1). Pregnenolone and dehydroepiandrosterone are so-called neurosteroids, an enigmatic class of compounds that are and metabolic roles P. M. Rev. 2001; PubMed Scopus Google Scholar); thus, hypothesis under is that CYP7B1 in There is as yet that or dehydroepiandrosterone in CYP7B1 knock-out the of CYP7B1 in these steroids from the brain and versus other enzymes that these substrates such as is A case for CYP7B1 in the be the of with spastic paraplegia type but whether this is caused by in steroid versus oxysterol remains to be determined. A steroid substrate of CYP7B1 is (7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), a 19-carbon steroid that is an for the estrogen receptor Carlsson K. E. J. S. Gustafsson J.A. 1997; PubMed Scopus Google Scholar). with other substrates, CYP7B1 to (Fig. M. Warner M. Gustafsson J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar), but the of this is the as that for 7α-hydroxylation, inactivation of the Loss of CYP7B1 in from line of knock-out mice (7Rose K. Allan A. Gauldie S. Stapleton G. Dobbie L. Dott K. Martin C. Wang L. Hedlund E. Seckl J.R. Gustafsson J.A. Lathe R. J. Biol. Chem. 2001; 276: 23937-23944Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) to prostates Z. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 13589-13594Crossref PubMed Scopus (295) Google Scholar) and to failure in female mice Y. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 2814-2819Crossref PubMed Scopus (45) Google Scholar). In both these reproductive tract are to which is to accumulate in the absence of CYP7B1 and to of the estrogen receptor Z. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 13589-13594Crossref PubMed Scopus (295) Google Scholar, 20Omoto Y. Lathe R. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 2814-2819Crossref PubMed Scopus (45) Google Scholar). The oxysterol 27-hydroxycholesterol is a estrogen receptor of the receptor in the M. Domoto H. Gormley A.K. Yuhanna I.S. Cummins C.L. Javitt N.B. Korach K.S. Shaul P.W. Mangelsdorf D.J. Nat. Med. 2007; 13: 1185-1192Crossref PubMed Scopus (317) Google Scholar) and the receptor in the absence of estrogen in and other lines C.D. Umetani M. Shaul P.W. Mangelsdorf D.J. McDonnell D.P. Mol. Endocrinol. 2008; 22: 65-77Crossref PubMed Scopus (226) Google Scholar). In agreement with this estrogen receptor CYP7B1 knock-out mice (8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), which accumulate 27-hydroxycholesterol in and show in gene expression in the and in M. Domoto H. Gormley A.K. Yuhanna I.S. Cummins C.L. Javitt N.B. Korach K.S. Shaul P.W. Mangelsdorf D.J. Nat. Med. 2007; 13: 1185-1192Crossref PubMed Scopus (317) Google Scholar). is not yet known whether these phenotypes arise from a failure of CYP7B1 to 27-hydroxycholesterol in the or in exists the of a of CYP7B1, to selectively the estrogen receptor suggested that this steroid was in human and the receptor C. Ross M. Chapman K.E. Andrew R. Bollina P. Seckl J.R. Habib F.K. J. Clin. Endocrinol. Metab. 2004; 89: 2928-2935Crossref PubMed Scopus (43) Google Scholar), a to the receptor in human kidney H. Holmberg L. Axelson M. Norlin M. FEBS J. 2008; 275: 1778-1789Crossref PubMed Scopus (31) Google Scholar). Both studies on in and to is in vivo to a physiological role for dehydroepiandrosterone in estrogen receptor of cholesterol and the subsequent synthesis of 25-hydroxycholesterol U. Olofsson K.E. Carlsson A.M. Gong M. Golenbock D.T. Rooyackers O. Fläring U. Björkbacka H. J. Lipid Res. 2009; 50 (in press)Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 26Bauman D.R. Bitmansour A.D. McDonald J.G. Thompson B.M. Russell D.W. Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (in press)Crossref PubMed Scopus (251) Google Scholar). The oxysterol is from the and the of by B two of B and of a gene that is for synthesis. This role is by the that cholesterol knock-out mice, which have higher than normal levels of in their sera and CYP7B1 knock-out mice, which accumulate the oxysterol (8Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), have levels of this CYP7B1 expression is induced in mouse and human by that are of and other of the J. A. A.M. 2005; PubMed Scopus Google Scholar, I. L. A. J. Biochem. PubMed Scopus Google Scholar). This may the to 25-hydroxycholesterol by As noted above, a role for CYP7B1 in bile salt synthesis was suggested by studies in the This function was confirmed with the of an with liver failure from an in the CYP7B1 gene K.D. Schwarz M. O'Connell N.C. Lund E.G. Davis D.L. Lathe R. Thompson H.R. Weslie Tyson R. Sokol R.J. Russell D.W. J. Clin. Invest. 1998; 102: 1690-1703Crossref PubMed Scopus (304) Google Scholar). that oxysterols and other bile salt in this bile salts a at codon in exon of the gene (Fig. which a protein that enzyme A with a similar but resulting from a at codon in exon of the CYP7B1 gene was I. A. A. H. H. J. 2008; PubMed Scopus Google Scholar). The of oxysterols and other bile salt in these was to have caused to the liver, these the of CYP7B1 in bile salt synthesis and the role of the enzyme in the inactivation of into CYP7B1 in from a of that the spastic paraplegia type was also caused by mutations in the CYP7B1 gene K. Warner Y. H. A. J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). confirmed R. M. A. A. C. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, R. E. M. S. S. M. L. C. 2009; PubMed Scopus (45) Google Scholar, C. A. A. C. J. C. M. S. L. J. O. P. I. C. C. A. A. 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G. 2009; PubMed Scopus Google Scholar). mutations in the gene to two with as as liver failure in and progressive in and are not caused by different mutations in the as the are found in with liver failure and spastic paraplegia type (Fig. are caused by of enzyme activity of function mutations are found associated with both A hypothesis is that the two from the of different CYP7B1 substrates, oxysterols in liver failure and steroids or another in spastic paraplegia type An in a might to synthesis of the oxysterol 25-hydroxycholesterol U. Olofsson K.E. Carlsson A.M. Gong M. Golenbock D.T. Rooyackers O. Fläring U. Björkbacka H. J. Lipid Res. 2009; 50 (in press)Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 26Bauman D.R. Bitmansour A.D. McDonald J.G. Thompson B.M. Russell D.W. Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (in press)Crossref PubMed Scopus (251) Google Scholar), which, in the absence of by CYP7B1, to liver a different steroid synthesis might by an as yet which to spastic paraplegia type of cytochrome P450 are not to Loss of a sterol that in oxysterol and bile salt synthesis (2Russell D.W. Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1493) Google Scholar), liver in A. E. A. G. R. J. Metab. 2002; PubMed Scopus Google Scholar, G. Setchell K. J. A. P. J. Metab. 2009; (in Scholar) but a progressive and other in a majority of I. E. The and of Scholar). substrates in these bile accumulate in with liver the hydrophobic sterol in the of There are to be by CYP7B1 which substrates of the enzyme in spastic paraplegia type is and a of 25-hydroxycholesterol a of liver failure in with CYP7B1 is liver a but in with spastic paraplegia type CYP7B1 knock-out mice of and the of or new enzyme substrates in the what are the biochemical properties of purified does the three-dimensional structure of CYP7B1 with cholesterol 7α-hydroxylase and what of the enzymes their substrate The the identification of CYP7B1 have a of this and is to and Mangelsdorf for of the