摘要:

In mouse hepatoma Hepa‐1c1c7 cultures, polycyclic aromatic compounds such as benzol[a]pyrene and 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD; dioxin) activate theCyp1a‐1(cytochrome P1450) andNmo‐1[NAD(P)H:menadione oxidoreductase] genes, two members of the aromatic hydrocarbon (Ah)‐responsive gene battery. Mevinolin is known to inhibit 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase (EC 1.1.1.34), the rate‐limiting step in cholesterol biosynthesis. We show here that in the absence of TCDD, mevinolin markedly increasesCyp1a‐1transcription, CYP1A1 mRNA and protein levels and enzyme activity, and NMO1 mRNA concentrations. Addition of mevalonate, the product of HMG‐CoA reductase activity, fails to reverse the effects of mevinolin. In fact, when used at high concentrations, mevalonate activatesCyp1a‐1transcription. Mevinolin‐inducedCyp1a‐1gene activation: (1) occurs independently of the lipid content of the growth medium, (2) is not suppressed by adding 25‐hydroxycholesterol, which blocks MHG‐CoA reductase activity, and (3) requires a functional Ah receptor and unimpaired nuclear translocation of the receptor. It is possible that an unknown metabolite (or metabolites) of mevinolin activatesCyp1a‐1expression and that high concentrations of mevalonate act via the same mechanism. Using chimaeric plasmids that contain different lengths ofCyp1a‐15′ flanking regions fused to the bacterial neomycin (neo) gene, we find that the mevinolin effect onCyp1a‐1induction requires the 5′ flanking sequences between ‐1647 and ‐824, which are also needed for TCDD induction. Mevinolin, however, is not a ligand for the Ah receptor. Gel mobility shift assays revealed thatCyp1a‐1activation caused by mevinolin does not involve the ligand‐dependent formation of a functional Ah receptor‐dependent DNA‐binding complex, but instead appears to be correlated with release of a putative repressor from its cognate DNA site. Our results suggest that the basel level ofCyp1a‐1transcription is maintained by an unknown negative regulatory factor. We propose thatCyp1a‐1transcriptional activation can result not only from induction by polycyclic aromatic compounds but also from derepression by mevinolin, independent of HMG‐CoA reductase inhibition.—Puga, A.; Ray‐Chaudhuri, B.; Nebert, D. W. Transcriptional derepression of the murineCyp1a‐1gene by mevinolin.FASEB J.6: 777‐785; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1311272

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The filling state of the intracellular Ca2+stores of rat thymocytes regulates plasma membrane permeability to Mn2+, used here as a Ca2+surrogate for plasma membrane Ca2+channels. Emptying of the Ca2+stores accelerated Mn2+entry about 10‐fold, and refilling with Ca2+restored low Mn2+permeability. The acceleration of Mn2+entry observed in cells with empty intracellular Ca2+stores was prevented by cytochrome P450 inhibitors. Imidazole antimycotics, especially econazole and miconazole, were the most potent inhibitors (IC50≌ 10–6m). The inhibitor sensitivity profile was similar to IA‐type cytochrome P450. Calmodulin antagonists increased the plasma membrane permeability to Mn2+in cells with filled Ca2+stores, and this effect was also blocked by imidazole antimycotics. On this basis, we propose a model in which activation of a cytochrome P450, situated at the Ca2+stores, opens a plasma membrane Ca2+pathway. This activity would be inhibited by Ca2+inside the stores by a calmodulin‐dependent mechanism.—Alvarez, J.; Montero, M.; Garcia‐Sancho, J. Cytochrome P450 may regulate plasma membrane Ca2+permeability according to the filling state of the intracellular Ca2+stores.FASEB J.6: 786‐792; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537469

出版商:Wiley    

年代:1992

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/j.1530-6860.1992.tb93346.x

出版商:Wiley    

年代:1992

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537470

出版商:Wiley    

年代:1992

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/j.1530-6860.1992.tb93347.x

出版商:Wiley    

年代:1992

数据来源: WILEY