Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH) S-transferases (GSTs) have an important role in the detoxification of (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the ultimate carcinogen of benzo[a]pyrene. However, the fate and/or biological activity of the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is not known. We now report that (-)-anti-BPD-SG is a competitive inhibitor (Ki 19 microM) of Pi-class isoenzyme mGSTP1-1, which among murine hepatic GSTs is most efficient in the GSH conjugation of (+)-anti-BPDE. Thus the inhibition of mGSTP1-1 activity by (-)-anti-BPD-SG might interfere with the GST-catalysed GSH conjugation of (+)-anti-BPDE unless one or more mechanisms exist for the removal of the conjugate. The results of the present study indicate that (-)-anti-BPD-SG is transported across canalicular liver plasma membrane (cLPM) in an ATP-dependent manner. The ATP-dependent transport of (-)-anti-[3H]BPD-SG followed Michaelis-Menten kinetics (Km 46 microM). The ATP dependence of the (-)-anti-BPD-SG transport was confirmed by measuring the stimulation of ATP hydrolysis (ATPase activity) by the conjugate in the presence of cLPM protein, which also followed Michaelis-Menten kinetics. In contrast, a kinetic analysis of ATP-dependent uptake of the model conjugate S-[3H](2,4-dinitrophenyl)-glutathione ([3H]DNP-SG) revealed the presence of a high-affinity and a low-affinity transport system in mouse cLPM, with apparent Km values of 18 and 500 microM respectively. The ATP-dependent transport of (-)-anti-BPD-SG was inhibited competitively by DNP-SG (Ki 1.65 microM). Likewise, (-)-anti-BPD-SG was found to be a potent competitive inhibitor of the high-affinity component of DNP-SG transport (Ki 6.3 microM). Our results suggest that GST-catalysed conjugation of (+)-anti-BPDE with GSH, coupled with ATP-dependent transport of the resultant conjugate across cLPM, might be the ultimate detoxification pathway for this carcinogen.
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PMID:ATP-dependent transport of glutathione conjugate of 7beta, 8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in murine hepatic canalicular plasma membrane vesicles. 962 Aug 85

Steroids administrated antenatally to the mothers improve postnatal outcomes of the newborns with pleiotropic effects. Furthermore steroids have been used in preterm infants to prevent or treat chronic lung disease. Synthetical glucocorticoids readily cross placental barrier and reach significant pharmacologic levels in the fetus: besides their well known pulmonary effects they have a concomitant maturational effect of postnatal renal function in preterm infants both with a direct and indirect effect. Endogenous and exogenous glucocorticoids play a role in the maintenance of glomerular filtration (GFR). The antenatal administration of steroids increases the GFR, in association to the maturation of the tubular function. According to different studies the improvement of renal function, expressed by the increase of GFR, is only partially referable to the increase of MAP and the improvement of the cardiovascular status, while it was imputable to a direct renal effect of the steroids, especially on the renal blood flow, on functional glomerular surface area available for filtration and on the glomerular filtrate of the single cortical nephron. However debate remains about the mechanism through which steroids would act on the renal vascular smooth muscolature. The increase the GFR observed after the antenatal administration of glucocorticoids in premature fetuses is also accompanied by an increase of urinary flow and of fractional excretion of sodium. Glucocorticoids would increase the proximal reabsorption of sodium increasing directly the function and the expression of the sodium transporters and both indirectly and directly increasing the activity of Na-K-ATPase. In extremely low weight antenatal administration of betamethasone or dexamethasone was associated with lower estimated insensible water loss, secondary to a direct maturational effect in the skin epithelial barrier, as well as an increased reabsorption of the fetal lung fluid. Moreover antenatal glucocorticoid administration was associated, at birth, to a significant suppression of plasma renin activity and angiotensin II in comparison to the controls. Despite the wide use of the steroidal therapy in the prevention of the bronchopulmonary dysplasia, only few articles, in literature, analyse the effects of glucocorticoids on postnatal renal function, such as the increase in urinary flow. The authors think that steroids contribute in a meaningful way to the clinical improvement observed in children with BPD through the maturative action on the premature kidney with effect both at glomerular and tubular level.
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PMID:Renal effects of antenatally or postnatally administered steroids. 1198 24

The most common form of newborn chronic lung disease, bronchopulmonary dysplasia (BPD), is thought to be caused by oxidative disruption of lung morphogenesis, which results in decreased pulmonary vasculature and alveolar simplification. Although cellular redox status is known to regulate cellular proliferation and differentiation, redox-sensitive pathways associated with these processes in developing pulmonary epithelium are unknown. Redox-sensitive pathways are commonly regulated by cysteine thiol modifications. Therefore two thiol oxidoreductase systems, thioredoxin and glutathione, were chosen to elucidate the roles of these pathways on cell death. Studies herein indicate that thiol oxidation contributes to cell death through impaired activity of glutathione-dependent and thioredoxin (Trx) systems and altered signaling through redox-sensitive pathways. Free thiol content decreased by 71% with hyperoxic (95% oxygen) exposure. Increased cell death was observed during oxygen exposure when either the Trx or the glutathione-dependent system was pharmacologically inhibited with aurothioglucose (ATG) or buthionine sulfoximine, respectively. However, inhibition of the Trx system yielded the smallest decrease in free thiol content (1.44% with ATG treatment vs 21.33% with BSO treatment). Although Trx1 protein levels were unchanged, Trx1 function was impaired during hyperoxic treatment as indicated by progressive cysteine oxidation. Overexpression of Trx1 in H1299 cells utilizing an inducible construct increased cell survival during hyperoxia, whereas siRNA knockdown of Trx1 during oxygen treatment reduced cell viability. Overall, this indicated that a comparatively small pool of proteins relies on Trx redox functions to mediate cell survival in hyperoxia, and the protective functions of Trx1 are progressively lost by its oxidative inhibition. To further elucidate the role of Trx1, potential Trx1 redox protein-protein interactions mediating cytoprotection and cell survival pathways were determined by utilizing a substrate trap (mass action trapping) proteomics approach. With this method, known Trx1 targets were detected, including peroxiredoxin-1as well as novel targets, including two HSP90 isoforms (HSP90AA1 and HSP90AB1). Reactive cysteines within the structure of HSP90 are known to modulate its ATPase-dependent chaperone activity through disulfide formation and S-nitrosylation. Whereas HSP90 expression is unchanged at the protein level during hyperoxic exposure, siRNA knockdown significantly increased hyperoxic cell death by 2.5-fold, indicating cellular dependence on HSP90 chaperone functions in response to hyperoxic exposure. These data support the hypothesis that hyperoxic impairment of Trx1 has a negative impact on HSP90-oxidative responses critical to cell survival, with potential implications for pathways implicated in lung development and the pathogenesis of BPD.
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PMID:Thioredoxin-1 redox signaling regulates cell survival in response to hyperoxia. 2510 6