ライフサイエンスコーパス: CYP3A

1 CYP3A activation of MMDX abolished the parent drug's res

2 CYP3A activity is the sum activity of the family of CYP3

3 CYP3A enzymes are extremely versatile and are inducible

4 CYP3A enzymes metabolize endogenous hormones and chemoth

5 CYP3A inhibition was determined from the impairment of n

6 CYP3A metabolic activity was significantly induced by Mi

7 CYP3A metabolism generates epipodophyllotoxin catechol a

8 CYP3A substrates inhibited the protein aggregation and s

9 CYP3A, the most important family of drug-metabolizing en

10 CYP3A-activated MMDX displayed a comparatively high intr

11 cipitation analyses revealed a basal 52% 35S-CYP3A loss over 6 h, which was stabilized by both protea

12 s dexamethasone [strong cytochrome P-450 3A (CYP3A) inducer] or triamcinolone acetonide (weak CYP3A i

13 ensively metabolized by cytochrome P-450 3A (CYP3A) isozymes, commonly used medications that inhibit

14 es and/or inhibitors of cytochrome P-450 3A (CYP3A).

15 n intestinal and hepatic cytochrome P450 3A (CYP3A) activity.

16 e-treated rats will form cytochrome P450 3A (CYP3A) aggregates when incubated at 37 degrees C.

17 rile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chem

18 Cytochrome P450 3A (CYP3A) is an enzyme of paramount importance to drug meta

19 Cytochrome P450 3A (CYP3A) is the most abundant CYP450 enzyme in the liver a

20 Human cytochrome P450 3A (CYP3A) members are major drug-metabolizing enzymes in th

21 Many genes of the cytochrome P450 3A (CYP3A) subfamily, including several human and rat isofor

22 rease in the activity of cytochrome P450 3A (CYP3A), which catalyzes side-chain hydroxylations of bil

23 The human liver cytochromes P450 3A (CYP3As), orthologous to the rat glucocorticoid inducible

24 rea under the time-concentration curve for a CYP3A substrate.

25 T>C (P<0.05) and 4beta-hydroxycholesterol, a CYP3A activity marker (adjusted R(2)=0.47).

26 of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.

27 basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) lev

28 ic p97 knockdown almost completely abrogated CYP3A extraction into the cytosol, resulting in a signif

29 se of P-gp inhibitors with minimal or absent CYP3A inhibitory effects should decrease the impact of d

30 th biochemically and genetically to activate CYP3A genes, while similar studies have established cons

31 phan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elemen

32 Stabilization of a functionally active CYP3A after RNAi knockdown of either of the E3s, coupled

33 d in increased levels of functionally active CYP3A, thereby challenging the previous notion that E3 r

34 97 interactions were greatly magnified after CYP3A suicidal inactivation (which accelerates UPD), and

35 those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the stu

36 meat are substrates for inducible CYP1A and CYP3A enzymes and for P-glycoprotein.

37 display an increased expression of CYP2B and CYP3A proteins.

38 They were reduced by inhibition of CYP2D and CYP3A enzymes.

39 chrome P450 enzymes of subfamilies CYP2D and CYP3A were inhibited before intravenous injection of [(1

40 the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expressi

41 conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol

42 RNA levels did not correlate with CYP2E1 and CYP3A activities.

43 quivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycin N-demethylase

44 CYP3A inhibition and the IC50s for P-gp and CYP3A inhibition allowed comparison of the relative inhi

45 mine whether the ability to inhibit P-gp and CYP3A is, in fact, linked and whether specific P-gp inhi

46 nd between the extent of P-gp inhibition and CYP3A inhibition, and the ratio of the IC50 for CYP3A in

47 tion, as well as of CYP3A protein levels and CYP3A-dependent testosterone 6beta-hydroxylation.

48 Microsomal CYP2E1, CYP2C-like, and CYP3A-like protein levels were also decreased in both st

49 bundant P-450 enzyme in the human liver, and CYP3A enzymes metabolize more than 50% of prescription d

50 or inducers of CYP2B (PB; phenobarbital) and CYP3A enzymes (DX; dexamethasone), isoforms induced by c

51 ted by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influ

52 1, but other P450 enzymes such as CYP2C8 and CYP3As also contribute to atRA 4-hydroxylation.

53 Triacetyloleandomycin and anti-CYP3A antibody inhibited midazolam hydroxylation by 53%

54 cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of ster

55 We used midazolam and fexofenadine to assess CYP3A (intestinal and hepatic) and drug transport, respe

56 levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymp

57 MMDX was rapidly activated by CYP3A at low ( approximately 1-5 nM) prodrug concentrati

58 gs demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-perme

59 (a reaction characteristically catalyzed by CYP3A enzymes) was estimated to be somewhat lower than t

60 ion of cortisol to 6 beta-hydroxycortisol by CYP3A may mediate increased tubular reabsorption of sodi

61 2C19, respectively, with some involvement by CYP3A.

62 oxides, which are efficiently metabolized by CYP3A.

63 one or more anticancer drugs metabolized by CYP3A.

64 mice, and showed that DDC is metabolized by CYP3A.

65 to the expected and previously characterized CYP3A pathway; rather, it is associated with a robust in

66 Therefore, we characterized CYP3A activity in a bank of microsomes from human kidney

67 We compared CYP3A metabolism of erythromycin (a Pgp substrate) using

68 By contrast, no corresponding CYP3A stabilization was detected with either ALD inhibit

69 strate specificities of PXR and its critical CYP3A target gene.

70 on days 1, 5, and 12 and analyzed for CYP1A, CYP3A, and P-glycoprotein messenger RNA (mRNA) and prote

71 and immunoreactive protein but not of CYP1A, CYP3A, or CYP4A.

72 r bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase

73 cess was specific for P-450s CYP1A2, CYP2E1, CYP3A, and CYP4A and was not demonstrated to be involved

74 evels several female-predominant liver CYPs (CYP3A, CYP2B, and testosterone 6beta-hydroxylase).

75 The cytochrome CYP3A gene products, expressed in mammalian liver, are e

76 12alpha-triol (triol), a cholesterol-derived CYP3A substrate, is a potent PXR agonist that effectivel

77 Little detectable CYP3A accumulated in the cytosol, even after concomitant

78 of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D.

79 gest that after extended periods of elevated CYP3A expression, microsomal factors are induced that ca

80 This prompted us to ask whether endogenous CYP3A substrates also serve as PXR ligands.

81 of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification.

82 Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4

83 with a corresponding approximately 2.5-fold CYP3A stabilization.

84 3A inhibition, and the ratio of the IC50 for CYP3A inhibition to the IC50 for P-gp inhibition varied

85 es was 10-fold higher than that required for CYP3A stabilization, we examined the effect of MG132 (0-

86 or, lithocholic acid is also a substrate for CYP3A enzymes.

87 , as we show here, a metabolic substrate for CYP3A hydroxylation.

88 thromycin, a widely used model substrate for CYP3A.

89 numerous medications that are substrates for CYP3A and Pgp.

90 Determination of the apparent Ki values for CYP3A inhibition and the IC50s for P-gp and CYP3A inhibi

91 The rat, mouse, and hamster CYP3A genes are mixed among several rodent CYP3A subclad

92 onazole, potent inhibitor of gut and hepatic CYP3A, has been shown to increase tacrolimus bioavailabi

93 Because hepatic CYP3A activity also seems to be induced during human pre

94 As expected, hepatic CYP3A activity was reduced in cirrhosis.

95 )CO(2) in the breath as a measure of hepatic CYP3A activity.

96 tion, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavaila

97 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A

98 e induced that catalyze the formation of HMM CYP3A conjugates that contain ubiquitin.

99 and the cytosol-dependent degradation of HMM CYP3A.

100 ubstrates inhibited the formation of the HMM CYP3A and the cytosol-dependent degradation of HMM CYP3A

101 sol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteas

102 in, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a

103 s of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that

104 system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not al

105 /polymerase chain reaction analysis of human CYP3A gene expression.

106 dy to demonstrate that a member of the human CYP3A gene family contains an enhancer that binds the GC

107 Immunoprecipitated CYP3A contained HMM ubiquitin.

108 mals had equivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycin N-d

109 terindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many

110 1 do not display a corresponding increase in CYP3A activity and are stricken with the disease cerebro

111 h E3s are indeed physiologically involved in CYP3A ERAD/UPD in cultured rat hepatocytes.

112 , thereby documenting a major role of p97 in CYP3A extraction and delivery to the 26 S proteasome dur

113 standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximatel

114 Cytochrome P450 (CYP) enzymes, including CYP3A, and multiple intestinal and hepatic drug transpor

115 tery of PXR target genes in liver, including CYP3A, Oatp2, and UGT1A1.

116 ohexy lamine (BIBX 79) selectively increased CYP3A mRNA and immunoreactive protein contents, with max

117 R is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA,

118 ally diverse collection of drugs that induce CYP3A.

119 Furthermore, MG-262-induced CYP3A stabilization was associated with its polyubiquity

120 Ro 48-8071-inducible CYP3A mRNA expression was restored when pravastatin-trea

121 t cyclase inhibitors are capable of inducing CYP3A expression in primary cultured rat and mouse hepat

122 ward these nuclear receptors could influence CYP3A gene expression.

123 p inhibitors with limited ability to inhibit CYP3A can be identified.

124 All compounds inhibited CYP3A with apparent Ki values of between 0.3 and 76 micr

125 at prodrug cleavage proceeded via an initial CYP3A-catalyzed oxidation to an intermediate ring-opened

126 ty, but its effect on hepatic and intestinal CYP3A in humans is not known.

127 ate alcohol consumption may cause intestinal CYP3A induction.

128 dazolam as a result of diminished intestinal CYP3A activity.

129 5-D3 and VDR induce expression of intestinal CYP3A by binding of the activated VDR-RXR heterodimer to

130 New animal models are needed to investigate CYP3A functions, especially for drug metabolism.

131 an inactivator of cytochrome P450 isoenzyme CYP3A without anti-HIV activity) and a new integrase inh

132 glucocorticoid and can be inhibited by known CYP3A inhibitors.

133 rate that the down-regulation of CYP2C-like, CYP3A-like and CYP2E1 proteins and mRNAs, in the endotox

134 CYP3A4 and its mammalian liver CYP3A orthologs are endoplasmic reticulum (ER)-anchored

135 ndicate that teleost, diapsid, and mammalian CYP3A genes have undergone independent diversification a

136 ients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially lead

137 centration-dependence of Ro 48-8071-mediated CYP3A mRNA induction corresponded to the cellular conten

138 Cyclase inhibitor-mediated CYP3A mRNA induction was eliminated when primary culture

139 ceptor PXR and demonstrated that it mediates CYP3A induction.

140 here is a significant increase in microsomal CYP3A dependent steroid 6 beta-hydroxylase activity but

141 o be a regioselective inhibitor of midazolam CYP3A metabolism.

142 Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical models, but thei

143 Moreover, CYP3A plays an important role in chemical metabolism, to

144 Most CYP3A diversity is the product of recent gene duplicatio

145 wed by significant increases in CYP3A1 mRNA, CYP3A-immunoreactive microsomal protein and total micros

146 t-5-en-17-one.HCl (U18666A) to induce murine CYP3A were abolished in hepatocyte cultures prepared fro

147 Such native CYP3A-p97 interactions were greatly magnified after CYP3

148 cin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medicat

149 with which other steroidal and nonsteroidal CYP3A inducers have been shown to compete, indicates tha

150 this study demonstrate that there is a novel CYP3A member expressed in human tissues, although its re

151 amplification technology was used on a novel CYP3A-like exon 1 sequence detected during the reverse t

152 The expression and activity of CYP3A, an enzyme responsible for active androgen clearan

153 Addition of CYP3A substrates inhibited the formation of the HMM CYP3

154 The amount of CYP3A protein in liver was inversely related to the gene

155 Immunoblotting analyses of CYP3A immunoprecipitates after PFA-cross-linking reveale

156 Analysis of CYP3A expression and activity was performed on lacrimal

157 lophosphamide 4-hydroxylation, as well as of CYP3A protein levels and CYP3A-dependent testosterone 6b

158 Our characterization of CYP3A degradation has indicated that CYPs 3A incur ubiqu

159 th the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006).

160 ilability can be an important determinant of CYP3A metabolism of numerous medications that are substr

161 used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, t

162 n that E3 recognition and subsequent ERAD of CYP3A proteins required ab initio their structural and/o

163 MDR1, might influence hepatic expression of CYP3A or other cytochromes P-450 (P-450s) because Pgp ca

164 ad reduced basal and inducible expression of CYP3A.

165 nf4alpha had reduced or absent expression of CYP3A.

166 determinant of drug-inducible expression of CYP3A.

167 oprotein (Pgp) could influence the extent of CYP3A-mediated metabolism of erythromycin, a widely used

168 ctivity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically

169 e stress is a key factor in the formation of CYP3A aggregates in incubated microsomes and in a recons

170 es in liver expression of different forms of CYP3A.

171 turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the pot

172 ibited potent time-dependent inactivation of CYP3A, with the mechanism of inactivation occurring thou

173 nd Cmin by 46%, consistent with induction of CYP3A by efavirenz.

174 of the mouse PXR gene abolishes induction of CYP3A by prototypic inducers such as dexamethasone or pr

175 The induction of CYP3A enzymes is species-specific, and we have postulate

176 erexpressing clones, rifampicin induction of CYP3A mRNA and protein was decreased and required greate

177 of rifampicin were required for induction of CYP3A proteins, and the magnitude of CYP3A induction was

178 use of erythromycin and strong inhibitors of CYP3A should be avoided.

179 any P-gp inhibitors are potent inhibitors of CYP3A, a varying degree of selectivity is present.

180 h the concurrent use of strong inhibitors of CYP3A.

181 sterdam had dramatically increased levels of CYP3A protein as well as other P-450s examined and of th

182 The magnitude of CYP3A induction by rifampicin was compared in the human

183 tion of CYP3A proteins, and the magnitude of CYP3A induction was greater at all doses of rifampicin i

184 e midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill childr

185 d no relationship with these measurements of CYP3A, but changed proportionally to expression of mdr1.

186 was measured by monitoring the metabolism of CYP3A probe substrates-namely, 7-benzyloxyquinoline (BQ)

187 es, dictates the species-specific pattern of CYP3A inducibility.

188 tructure of the gene dictates the pattern of CYP3A inducibility.

189 The role of Pgp in regulation of CYP3A expression in vivo was analyzed in mice carrying a

190 e but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consiste

191 aling pathways involved in the regulation of CYP3A, CYP2C, and CYP2D, which are critical enzymes in d

192 ctivity while having greatly reduced risk of CYP3A induction in humans.

193 e physiological and pharmacological roles of CYP3A, especially in drug and chemical metabolism in viv

194 We analyzed the 5'-flanking sequences of CYP3A genes from the rat (CYP3A23, CYP3A2), rabbit (CYP3

195 to the substrate-dependent stabilization of CYP3A observed in vivo.

196 rtant in substrate-mediated stabilization of CYP3A.

197 eptor, rather than the promoter structure of CYP3A genes, dictates the species-specific pattern of CY

198 Tacrolimus, a substrate of CYP3A, has low and variable bioavailability similar to c

199 NA was increased by insulin, whereas that of CYP3A was unaffected.

200 tudy helps provide a better understanding of CYP3A regulation and offers novel clues for the role of

201 m of SXR causes constitutive upregulation of CYP3A gene expression and enhanced protection against to

202 A or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in t

203 the species-specific effects of compounds on CYP3A gene expression.

204 und a biphasic MG132 concentration effect on CYP3A turnover: Stabilization at 5 to 10 muM with marked

205 her than deconvoluting the effect of P-gp on CYP3A-mediated metabolism.

206 ntration-dependent proteasomal inhibition on CYP3A turnover in cultured primary rat hepatocytes.

207 We evaluated the effect of uremia on CYP3A and transporter expression in vitro by incubating

208 gene encoding cytochrome P450 3A oxygenase (CYP3A) causes a prominent class of dangerous drug-drug i

209 Metabolism by cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp)-mediated efflux are two

210 ulators and substrates of cytochrome P4503A (CYP3A).

211 To assess the in vivo relevance of this p97-CYP3A association, we used lentiviral shRNAs to silence

212 Intriguingly, the accumulated parent CYP3A was functionally active, indicating that p97 can r

213 dicating that p97 can regulate physiological CYP3A content and thus influence its clinically relevant

214 by effectively regulating the physiological CYP3A content and consequently its function.

215 rong support for placement of the guinea pig CYP3A genes within the rodent CYP3A diversification.

216 mpound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further che

217 -hydroxymidazolam (1'-OHM) as a prototypical CYP3A-catalyzed reaction.

218 Luciferase induction by the prototypical CYP3A inducer pregnenolone 16alpha-carbonitrile was rest

219 zed purified rat CYP2E1 but not purified rat CYP3A were detected by enzyme-linked immunosorbent assay

220 Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug l

221 r-kappaB activation and consequently reduced CYP3A protein stability.

222 cid levels in the intestine by up-regulating CYP3A enzymes with 1,25(OH)2 D3 analogs may have therape

223 Consistent with the protein results, CYP3A catalytic activity measured as midazolam 1'- and 4

224 r CYP3A genes are mixed among several rodent CYP3A subclades, indicative of a complex history involvi

225 the guinea pig CYP3A genes within the rodent CYP3A diversification.

226 een WT and LCN mice in small intestinal (SI) CYP3A levels at 6 hours after the treatment.

227 cestral vertebrate genome contained a single CYP3A gene.

228 tor of CYP2C9) or troleandomycin (a specific CYP3A inhibitor) did not increase inhibition beyond that

229 bonyl-Leu-Leu-Leu-B(OH)(2) (MG262) stabilize CYP3A proteins.

230 short half-life and how substrates stabilize CYP3A.

231 At these high MG132 concentrations, such CYP3A suppression could be due to ER stress induction, s

232 , MG132 is indeed cytotoxic and can suppress CYP3A synthesis, a result confirmed by confocal immunofl

233 binding to cytochrome P450 isoenzyme system CYP3A induced extreme prolongation of tacrolimus metabol

234 rofiling by RNAi silencing demonstrates that CYP3A or 2C8 gene expression is specifically required fo

235 e after oral administration, suggesting that CYP3A function is not changed by ESRD.

236 The CYP3A enzymes metabolize a wide variety of chemically di

237 The CYP3A genes reside on chromosome 7q21 in a multigene clu

238 The CYP3A inhibitors used in the study were nitroimidazole a

239 The CYP3A subfamily of hepatic cytochromes P450, being engag

240 why MDZ is predominantly metabolized by the CYP3A enzyme subfamily.

241 Of the cytochrome P450 enzymes, the CYP3A subfamily is the most abundant in liver and intest

242 indings revealed the molecular basis for the CYP3A induction class of drug-drug interactions and prov

243 Variation in the CYP3A enzymes, which act in drug metabolism, influences

244 hrough a DNA response element located in the CYP3A promoter, and is activated by a structurally diver

245 The CYP3 gene family includes the CYP3A and CYP3B subfamilies.

246 ol fails to activate human PXR or induce the CYP3A-salvage pathway.

247 nsport is a critical element influencing the CYP3A inductive response.

248 id-or rifampicin-inducible expression of the CYP3A cytochromes P450, the dominant froms of this super

249 erindividual variability and ontogeny of the CYP3A enzymes, the most abundant phase I drug-metabolizi

250 is the ubiquitously expressed member of the CYP3A family in renal tissue.

251 ntagonist that induces the expression of the CYP3A family of steroid hydroxylases and modulates stero

252 expression of the xenobiotic enzymes of the CYP3A family.

253 The apparent coordinated coexpression of the CYP3A gene family and P-glycoprotein in the LS180 cells

254 major glucocorticoid-inducible member of the CYP3A gene family, have been identified.

255 plete coding sequence of a new member of the CYP3A gene subfamily, CYP3A43.

256 Members of the CYP3A subfamily represent the dominant CYP forms express

257 Two vital enzymes of the CYP3A subfamily, CYP3A4 and CYP3A5, are differentially e

258 In the presence of substrate, the CYP3A-mediated lipid hydroperoxide metabolism is inhibit

259 of the activated VDR-RXR heterodimer to the CYP3A PXR response element and promoting gene transcript

260 egulate the mRNA of enzymes belonging to the CYP3A subfamily, increasing the metabolism of a variety

261 tentiation ratios directly correlated to the CYP3A-dependent testosterone 6beta-hydroxylase activity

262 epatic protein, including but not limited to CYP3A and tryptophan 2,3-dioxygenase protein syntheses.

263 CYP3A5 represented greater than 50% of total CYP3A content in nearly all of the livers and jejuna tha

264 ant accumulation of parent and ubiquitinated CYP3A species that were firmly ER-tethered.

265 Raloxifene, a drug known to undergo CYP3A-mediated reactive metabolite formation and time-de

266 ; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those wh

267 antibiotic medications who had formerly used CYP3A inhibitors.

268 of metabolite profiles and experiments using CYP3A-specific inhibitors indicated that CYP3A4 was the

269 with medications that are metabolized using CYP3A and causes reversible declines in estimated glomer

270 clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance w

271 hat NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expres

272 A) inducer] or triamcinolone acetonide (weak CYP3A inducer) produced dose-dependent increases in luci

273 Such overlap raises the question of whether CYP3A inhibition is an intrinsic characteristic of P-gp

274 e studies provide a mechanistic model of why CYP3A has a relatively short half-life and how substrate

275 Animals treated with CYP3A inducers or inhibitor showed accelerated or dimini