Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of alpha-Hederin, a triterpenoid saponin which exists in some oriental herbs, on the expression of liver cytochrome P450s were examined in mice. The administration of alpha-Hederin to mice significantly decreased the hepatic content of P450 and the activities of microsomal ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, and aniline hydroxylase, representative activities of cytochrome-P4501A1, -P4501A2, and -P4502E1, respectively, in a dose- and time-dependent manner. However, pentoxyresorufin O-dealkylase, a representative activity of cytochrome P4502B1/2, was decreased to a lesser extent. alpha-Hederin also decreased inducible monooxygenase activities in the same manner. Suppressions of P450 isozyme expression occurred in alpha-Hederin treated hepatic microsomes, as determined by immunoblot analysis in a manner consistent with that of the enzyme activity levels. Levels of mRNA of P4501A1/2 and P4502B1/2 were also decreased by alpha-Hederin as shown by Northern blot analysis. In contrast, the level of P4502E1 mRNA in the liver of alpha-Hederin treated mice was unchanged. These results suggest that alpha-Hederin may act as a more specific suppressor for P4501A and P4502E1 than P4502B and that the suppression involves decreases in mRNA levels except in the case of P4502E1.
Biochem Mol Biol Int 1998 Dec
PMID:Suppression of constitutive and inducible cytochrome P450 gene expression by alpha-hederin in mice. 986 56

Current developments in experimental chemotherapy of Chagas' disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (inhibitors of sterol C14alpha demethylase), with particular selectivity against Trypanosoma cruzi and special pharmacokinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitological cure of this disease in its chronic phase. We also discuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas' disease. Although previous studies have suggested an important autoimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed immunological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a positive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for chagasic cardiomyopathy and confirm the importance of specific etiological treatment in the management of chronic chagasic patients.
J Mol Med (Berl) 1999 Mar
PMID:Chemotherapy of Chagas' disease: the how and the why. 1009 May 96

Drugs which suppress hepatic cholesterol biosynthesis are important therapeutic tools for lowering serum cholesterol, a major risk factor in coronary heart disease. With the goal of developing molecules that will effectively shut down cholesterol biosynthesis in hepatic tissue but allow for the buildup of the isoprenes needed for the biosynthesis of polyisoprenes other than sterols, we have designed and evaluated a series of lanosterol analogs to act as dual-action inhibitors of cholesterol biosynthesis. These sterols were predicted to act as competitive inhibitors of lanosterol 14alpha-methyl demethylase (P-450DM) and as partial suppressors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme in the pathway. Compounds which have been identified as dual-action inhibitors of cholesterol biosynthesis include analogs of the intermediates generated during the removal of the 14alpha-methyl group of lanosterol by P-450DM, aminolanosterols with the amine nitrogen placed in the vicinity of C-32, and lanosterol analogs with a ketone or oxime functionality at C-15. While some dual-action inhibitors require an active P-450DM for suppression of HMGR activity, others do not. The inability of some compounds to suppress HMGR activity in cells which lack P-450DM activity suggests either that these compounds require P-450DM for conversion to an active metabolite which then suppresses HMGR activity, or that they cause the accumulation of the natural demethylation intermediates resulting in the suppression of HMGR activity. Lanosterol analogs, in contrast to 25-hydroxycholesterol, do not inhibit transcription of the HMGR gene. Rather, they inhibit translation of the HMGR mRNA, and in most cases also accelerate the degradation of enzyme protein. The potential pharmacological utility of cholesterol biosynthesis inhibitors may be determined at least in part by their effects on LDL receptor (LDLR) activity. The transcriptional regulator 25-hydroxycholesterol suppresses both HMGR and LDLR activities, while the post-transcriptional regulatory lanosterol analogs exhibit a more desirable profile, lowering HMGR levels without suppressing LDLR expression, and in some cases actually enhancing cellular LDL metabolism. Lanosterol analogs which function as dual-action inhibitors of cholesterol biosynthesis promise to be useful not only as tools for dissecting the cellular regulation of cholesterol metabolism, but also as models for the development of safe, effective hypocholesterolemic agents.
Crit Rev Biochem Mol Biol 1999
PMID:Lanosterol analogs: dual-action inhibitors of cholesterol biosynthesis. 1033 89

Dihydrolanosterol (DHL) and its analogs have been studied extensively as cholesterol biosynthesis inhibitors. They inhibit specific steps in cholesterol synthesis by inhibiting lanosterol demethylase and by suppressing HMG-CoA reductase. The present study was designed to estimate the lymphatic absorption of DHL. For comparison, a cholesterol group was included. The left thoracic duct of male Wistar rats weighing between 210 and 230 g was cannulated. A lipid emulsion containing 0.75microCi of either [3H]-DHL or [3H]-cholesterol was given intragastrically. After the lipid meal, lymph was collected at 3 h intervals up to 9 h and then at 24 h. Radioactivity of DHL and cholesterol in the lymph was estimated. Lipid extracts of lymph specimens were also subjected to thin layer chromatography and fractions of DHL, cholesterol and their esters were isolated and the masses were estimated. There were no differences in lymph volumes between the two groups. However, absorption and esterification of DHL in lymph were significantly reduced compared with the cholesterol group. The marked decrease in the esterification of DHL is likely due to its poor absorption into the mucosal cell and subsequently into the lymphatic system. The amount of DHL available in the mucosal cell for esterification may be a limiting factor.
Res Commun Mol Pathol Pharmacol 1999 Jan
PMID:The lymphatic absorption of dihydrolanosterol and cholesterol in the rat. 1044 May 74

Hepatic P450s, named M-3 and M-4 were purified from phenobarbitone pretreated rhesus monkey. These demonstrated polypeptide molecular mass of 50 and 52.5 kDa and specific content of 12 and 20 nmol P450/mg protein, respectively. Both the isozymes demonstrated low spin state of heme. Antibodies raised against M-3 inhibited the activity of aminopyrine, erythromycin and ethylmorphine N-demethylase in the microsomes obtained from PB pretreated rhesus monkey by 76, 40 and 35%, respectively. M-4 did the same by 69, 85 and 79%, respectively. These observations indicated M-3 and M-4 to be the members of CYP2C and 3A subfamilies, respectively. These results were substantiated by the observations that M-3 metabolized aminopyrine whereas M-4 metabolized aminopyrine, erythromycin and ethylmorphine in the reconstituted system. Microsomal lipids and cytochrome b5 enhanced the rate of these reactions. Further confirmation to the identity of these isozymes was provided by N-terminal amino acid sequences. The first 10 N-terminal amino acid residues of M-3 were 90% similar to CYP2C20 and 2C9 and that of M-4 were 100 and 90% similar to CYP3A8 and 3A5, respectively. In conclusion, two isozymes of hepatic P450 purified from PB pretreated rhesus monkey belong to CYP2C and 3A subfamilies.
Mol Cell Biochem 1999 Aug
PMID:Purification and characterization of the hepatic CYP2C and 3A isozymes from phenobarbitone pretreated rhesus monkey. 1049 81

Lanosterol 14alpha-demethylase (CYP51) produces MAS sterols, intermediates in cholesterol biosynthesis that can reinitiate meiosis in mouse oocytes. As a cholesterogenic gene, CYP51 is regulated by a sterol/sterol-regulatory element binding protein (SREBP)-dependent pathway in liver and other somatic tissue. In testis, however, cAMP/cAMP-responsive element modulator CREMtau-dependent regulation of CYP51 predominates, leading to increased levels of shortened CYP51 mRNA transcripts. CREM-/- mice lack the abundant germ cell-specific CYP51 mRNAs in testis while expression of somatic CYP51 transcripts is unaffected. The mRNA levels of squalene synthase (an enzyme preceding CYP51 in cholesterol biosynthesis in testis of CREM-/- mice are unchanged as compared with wild-type animals, showing that regulation by CREMtau is not characteristic for all cholesterogenic genes expressed during spermatogenesis. The -334/+314 bp CYP51 region can mediate both the sterol/SREBP-dependent as well as the cAMP/CREMtau-dependent transcriptional activation. SREBP-1a from somatic cell nuclear extracts binds to a conserved CYP51-SRE1 element in the CYP51 proximal promoter. The cAMP-dependent transcriptional activator CREMtau from germ cell nuclear extracts binds to a conserved CYP51-CRE2 element while no SREBP-1 binding is observed in germ cells. The two regulatory pathways mediating expression of CYP51 describe this gene as a cholesterogenic gene (SREBP-dependent expression in liver and other somatic cells) and also as a haploid expressed gene (CREMtau-dependent expression in haploid male germ cells). While in somatic cells all genes involved in cholesterol biosynthesis are regulated coordinately by the sterol/SREBP-signaling pathway, male germ cells contain alternate routes to control expression of cholesterogenic genes.
Mol Endocrinol 1999 Nov
PMID:Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. 1055 87

A detailed analysis of the endogenous sterols present in the clinically relevant intracellular (amastigote) stages of Trypanosoma cruzi, is presented. The parasites were grown in cultured Vero cells in the absence or presence of different sterol biosynthesis inhibitors, including the C14alpha demethylase inhibitor ketoconazole and two inhibitors of delta24(25)-sterol methyl transferase, 20 piperidin-2-yl-5alpha-pregnan-3beta-20-R-diol (22,26-azasterol) and 24-(R,S),25-epiminolanosterol. Amastigotes were isolated and purified from their host cells and neutral lipids were extracted, separated and analyzed by chromatographic and mass spectrometric methods. Control (untreated) amastigotes contained as main endogenous sterols 24-methyl-cholesta-7-en-3beta-ol (ergosta-7-en-3beta-ol) and its 24-ethyl analog, plus smaller amounts of their precursor, ergosta-7,24(28)dien-3beta-ol; these cells also contained cholesterol (up to 80% by weight of total sterols), probably derived from host cells. Amastigotes that proliferated in the presence of 10 nM ketoconazole (minimal inhibitory concentration, MIC) for 24 h had a sharply reduced content of endogenous 4-desmethyl sterols with a concomitant accumulation of 24-methyl-dihydrolanosterol and 24-methylene-dihydrolanosterol. On the other hand, amastigotes incubated during the same period of time with the two inhibitors of 24(25)-SMT at their respective MICs (100-300 nM) accumulated large amounts of C27 sterols whose structure suggested, in the case of 22,26-azasterol, that delta14 sterol reductase was also inhibited. Ketoconazole produced a dose-dependent reduction in the incorporation of [2-(14)C]-acetate into the parasite's endogenous C4-desmethyl sterols with an IC50 of 50 nM, indistinguishable from the value reported previously for the extracellular epimastigote form. Taken together, the results showed that amastigotes have a simpler sterol biosynthetic pathway than that previously described for epimastigotes, lacking both delta5 and delta22 reductases. They also suggest that the 100-fold higher potency of antifungal azoles as antiproliferative agents against amastigotes, when compared with epimastigotes, is most probably due to a smaller pool of endogenous sterols in the intracellular parasites.
Mol Biochem Parasitol 1999 Oct 25
PMID:Sterol composition and biosynthesis in Trypanosoma cruzi amastigotes. 1058 83

Many organic solvents are frequently used as support solvents to dissolve chemicals in the study concerning drug metabolism mediated by cytochrome P450. However, some organic solvents used as the support solvents affect the chemical's metabolism. It has been reported that some organic solvents are metabolized by CYP2E1 or inhibit its enzymatic reaction. In this study we investigated the effects of organic solvents, such as acetonitrile (AN), dimethylsulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), polyethylene glycol (PEG) and propylene glycol (PG) on TMO (trimethadione) metabolism, which is mainly mediated by CYP2E1 in the rat. In the in vivo study, male SD rats were pretreated with an organic solvent intraperitoneally at a dosage of 0.5, 1 or 2 mmol/kg 1 hour before TMO administration orally at the dose of 4 mg/kg. After 2 hours, serum concentrations of TMO and DMO were determined by gas chromatography/flame detection (CG/FTD) and the serum DMO/TMO ratio was employed for assessment of the metabolic capacity of TMO. In the in vitro study, hepatic microsomal fraction was used as an enzyme source of TMO N-demethylase and enzyme activities were determined by the production of DMO. Pretreatment with DMSO and PG decreased the DMO/TMO ratio in a dose-related manner in vivo study. Furthermore, in vitro study TMO N-demethylase activity was inhibited by DMSO, EtOH and PG with different potency in a concentration related manner. However, no remarkable effects were observed by AN or PEG both in vivo and in vitro study. These results indicated that there are variations in the inhibitory effects of these organic solvents on CYP2E1-mediated metabolism and AN and PEG will be useful solvents to dissolve chemicals in the metabolic study mainly mediated by CYP2E1.
Res Commun Mol Pathol Pharmacol 1999
PMID:The effects of organic solvents on trimethadione n-demethylation in rats. 1063 15

We studied the long-term effects of streptozotocin-induced diabetes on tissue-specific cytochrome P450 (CYP) and glutathione-dependent (GSH-dependent) xenobiotic metabolism in rats. In addition, we also studied the effect of antidiabetic Momordica charantia (karela) fruit-extract feeding on the modulation of xenobiotic metabolism and oxidative stress in rats with diabetes. Our results have indicated an increase (35-50%) in CYP4A-dependent lauric acid hydroxylation in liver, kidney, and brain of diabetic rats. About a two-fold increase in CYP2E-dependent hepatic aniline hydroxylation and a 90-100% increase in CYP1A-dependent ethoxycoumarin-O-deethylase activities in kidney and brain were also observed. A significant increase (80%) in aminopyrene N-demethylase activity was observed only in rat kidney, and a decrease was observed in the liver and brain of diabetic rats. A significant increase (77%) in NADPH-dependent lipid peroxidation (LPO) in kidney of diabetic rats was also observed. On the other hand, a decrease in hepatic LPO was seen during chronic diabetes. During diabetes an increased expression of CYP1A1, CYP2E1, and CYP4A1 isoenzymes was also seen by Western blot analysis. Karela-juice feeding modulates the enzyme expression and catalytic activities in a tissue- and isoenzyme-specific manner. A marked decrease (65%) in hepatic GSH content and glutathione S-transferase (GST) activity and an increase (about two-fold) in brain GSH and GST activity was observed in diabetic rats. On the other hand, renal GST was markedly reduced, and GSH content was moderately higher than that of control rats. Western blot analyses using specific antibodies have confirmed the tissue-specific alterations in the expression of GST isoenzymes. Karela-juice feeding, in general, reversed the effect of chronic diabetes on the modulation of both P450-dependent monooxygenase activities and GSH-dependent oxidative stress related LPO and GST activities. These results have suggested that the modulation of xenobiotic metabolism and oxidative stress in various tissues may be related to altered metabolism of endogenous substrates and hormonal status during diabetes. The findings may have significant implications in elucidating the therapeutic use of antidiabetic drugs and management of Type 1 diabetes in chronic diabetic patients.
J Biochem Mol Toxicol 2000
PMID:Modulation of xenobiotic metabolism and oxidative stress in chronic streptozotocin-induced diabetic rats fed with Momordica charantia fruit extract. 1071 28

We determined whether the drug efflux protein P-glycoprotein (Pgp) could influence the extent of CYP3A-mediated metabolism of erythromycin, a widely used model substrate for CYP3A. We compared CYP3A metabolism of erythromycin (a Pgp substrate) using the erythromycin breath test in mice proficient and deficient of mdr1 drug transporters. We first injected mdr1(+/+) mice with [(14)C]N-methyl erythromycin and measured the rate of appearance of (14)CO(2) in the breath as a measure of hepatic CYP3A activity. Animals treated with CYP3A inducers or inhibitor showed accelerated or diminished (14)CO(2) in the breath, respectively. The erythromycin breath test was next administered to mdr1a(-/-) and mdr1a/1b(+/+) and (-/-) mice. These animals had equivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycin N-demethylase activity in liver microsomes. Nevertheless, the rate of (14)CO(2) appearance in the breath showed no relationship with these measurements of CYP3A, but changed proportionally to expression of mdr1. The average breath test (14)CO(2) area under the curves were 1.9- and 1.5-fold greater in mdr1a/1b(-/-) and mdr1a(-/-) mice, respectively, compared with (+/+) mice, and CER(max) was 2-fold greater in mdr1a/1b(-/-) compared with (+/+) mice. We conclude that Pgp, by limiting intracellular substrate availability can be an important determinant of CYP3A metabolism of numerous medications that are substrates for CYP3A and Pgp.
Mol Pharmacol 2000 Oct
PMID:Mdr1 limits CYP3A metabolism in vivo. 1099 59


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