There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.
This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.
In this study, we examined whether 1␣,25-dihydroxyvitamin D 3 (calcitriol), phenobarbital, and the antiretroviral drug efavirenz, drugs used by patient groups with high incidence of low bone mineral density, could affect the 25-hydroxylase activity or expression of human 25-hydroxylases in dermal fibroblasts and prostate cancer LNCaP cells. Fibroblasts express the 25-hydroxylating enzymes CYP2R1 and CYP27A1. LNCaP cells were found to express two potential vitamin D 25-hydroxylases-CYP2R1 and CYP2J2. The presence in different cells of nuclear receptors vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) was also determined. Phenobarbital suppressed the expression of CYP2R1 in fibroblasts and CYP2J2 in LNCaP cells. Efavirenz suppressed the expression of CYP2R1 in fibroblasts but not in LNCaP cells. CYP2J2 was slightly suppressed by efavirenz, whereas CYP27A1 was not affected by any of the two drugs. Calcitriol suppressed the expression of CYP2R1 in both fibroblasts and LNCaP cells but had no clear effect on the expression of either CYP2J2 or CYP27A1. The vitamin D 3 25-hydroxylase activity in fibroblasts was suppressed by both calcitriol and efavirenz. In LNCaP cells, consumption of substrate (1␣-hydroxyvitamin D 3 ) was used as indicator of metabolism because no 1␣,25-dihydroxyvitamin D 3 product could be determined. The amount of 1␣-hydroxyvitamin D 3 remaining in cells treated with calcitriol was significantly increased. Taken together, 25-hydroxylation of vitamin D 3 was suppressed by calcitriol and drugs. The present study provides new information indicating that 25-hydroxylation of vitamin D 3 may be regulated. In addition, the current results may offer a possible explanation for the impaired bone health after treatment with certain drugs.The metabolic activation of vitamin D is initiated by 25-hydroxylation of the side chain followed by a 1␣-hydroxylation. 1␣,25-Dihydroxyvitamin D 3 (calcitriol), the biologically most active form of vitamin D 3 , is known as a calciumregulating hormone but is involved also in other processes such as modulation of the immune system and cell proliferation and differentiation. At the moment, at least four enzymes capable of 25-hydroxylation of vitamin D 3 and/or vitamin D 2 have been described in humans, including the mitochondrial CYP27A1 and the microsomal CYP2R1, CYP2J2, and CYP3A4 (Ohyama and Yamasaki, 2004;Prosser and Jones, 2004). CYP3A4 is reported to prefer the nonphysiological form vitamin D 2 over vitamin D 3 (Gupta et al., 2004). Thus, several possible candidates for a vitamin D 3 25-hydroxylase have been suggested; from a regulatory perspective, however, the physiological roles of these proposed 25-hydroxylases remain poorly defined. In this context, it is interesting that vitamin D 3 25-hydroxylation occurs also in certain extrahepatic tissues (e.g., the prostate). Regulation of human vitamin D 3 25-hydroxylation may be particularly important in extrahepatic tissues and might be a means of controlling cellular le...
A 7␣-hydroxylation is necessary for conversion of both cholesterol and 27-hydroxycholesterol into bile acids. According to current theories, cholesterol 7␣-hydroxylase (CYP7A) is responsible for the former and oxysterol 7␣-hydroxylase (CYP7B) for the latter reaction. CYP7A is believed to have a very high substrate specificity whereas CYP7B is active toward oxysterols, dehydroepiandrosterone, and pregnenolone. In the present study, 7␣-hydroxylation of various oxysterols in liver and kidney was investigated. Surprisingly, human cholesterol 7␣-hydroxylase, CYP7A, expressed as a recombinant in Escherichia coli and COS cells, was active toward 20(S)-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol. This enzyme has previously been thought to be specific for cholesterol and cholestanol. A partially purified and reconstituted cholesterol 7␣-hydroxylase enzyme fraction from pig liver showed 7␣-hydroxylase activity toward the same oxysterols as metabolized by expressed recombinant human and rat CYP7A. The 7␣-hydroxylase activity toward 20(S)-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol in rat liver was significantly increased by treatment with cholestyramine, an inducer of CYP7A. From the present results it may be concluded that CYP7A is able to function as an oxysterol 7␣-hydroxylase, in addition to the previously known human oxysterol 7␣-hydroxylase, CYP7B. These findings may have implications for oxysterol-mediated regulation of gene expression and for pathways of bile acid biosynthesis. A possible use of 20(S)-hydroxycholesterol as a marker substrate for CYP7A is proposed.Oxysterols are important degradation products of cholesterol and are intermediates in biosynthesis of steroid hormones and bile acids. These compounds have a broad spectrum of biological effects including modulation of the activity of enzymes involved in cholesterol homeostasis (1-9). Primary bile acids are formed from cholesterol in the liver, either through the "neutral pathway" or the "acidic pathway," involving several cytochrome P450 enzymes. The first and rate-limiting reaction in the neutral pathway is a 7␣-hydroxylation by the cholesterol 7␣-hydroxylase (CYP7A), 1 an enzyme believed to be specific for cholesterol and cholestanol (10, 11). The first step of the acidic pathway is a 27-hydroxylation. 27-Hydroxycholesterol is further 7␣-hydroxylated by an oxysterol 7␣-hydroxylase (27-hydroxycholesterol 7␣-hydroxylase), which does not 7␣-hydroxylate cholesterol (12-17). A cDNA has been isolated encoding an oxysterol 7␣-hydroxylase (CYP7B), which catalyzes 7␣-hydroxylation of 25-hydroxycholesterol, 27-hydroxycholesterol, dehydroepiandrosterone, and pregnenolone (18 -21). In contrast to CYP7A, which is found only in the liver, CYP7B is present also in extrahepatic tissues and organs (21). It has recently been reported that several oxysterols including 20(S)-, 22(R)-, 25-, and 27-hydroxycholesterol are ligands of the liver X receptor (LXR), which functions as a ligand-dependent transcription factor in a het...
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