Proton pump-linked Mg2+-ATPase activity in isolated rat liver lysosomes

Dell’Antone, Paolo

doi:10.1016/0003-9861(88)90194-4

Cited by 15 publications

(7 citation statements)

References 57 publications

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“…The saturable uptake of quinine, fluvoxamine, and fluoxetine was substantially, but incompletely, reduced after pretreatment of hepatocytes with the ATP inhibitor, FCCP, providing evidence of involvement of an active process. Partial inhibition of saturable uptake does not necessarily indicate involvement of an additional, nonactive, process; partial inhibition by several ATP inhibitors has been observed in other studies (D'Souza et al, 1987;Dell'Antone, 1988;Van Dyke, 1993). Also, there is evidence to support the specificity of the FCCP cellular effect in reducing ATP (Yamazaki et al, 1993(Yamazaki et al, , 1996.…”

Section: Discussionmentioning

confidence: 88%

“…There have been numerous reports of the phenomenon of trapping by lysosomes of basic compounds including imipramine and propranolol (Moseley and Van Dyke, 1995;Ishizaki et al, 1996;Siebert et al, 2004). Maintenance of the low lysosomal pH is ATP-dependent (D'Souza et al, 1987;Dell'Antone, 1988;Moseley and Van Dyke, 1995;Strazzabosco and Boyer, 1996), and thus, the possibility that the saturable component of uptake represents the lysosomal uptake is supported by the data for uptake in cells pretreated with the ATP inhibitor, FCCP. There are numerous inhibitors of ATP-dependent processes; FCCP, however, has been shown to inhibit lysosomal pH maintenance, specifically (Dell'Antone, 1988).…”

Section: Downloaded Frommentioning

confidence: 96%

“…Maintenance of the low lysosomal pH is ATP-dependent (D'Souza et al, 1987;Dell'Antone, 1988;Moseley and Van Dyke, 1995;Strazzabosco and Boyer, 1996), and thus, the possibility that the saturable component of uptake represents the lysosomal uptake is supported by the data for uptake in cells pretreated with the ATP inhibitor, FCCP. There are numerous inhibitors of ATP-dependent processes; FCCP, however, has been shown to inhibit lysosomal pH maintenance, specifically (Dell'Antone, 1988). Saturation may be due to pH elevation, at high concentrations of sequestered ions, by exhaustion of ATP-dependent buffering capacity.…”

Section: Downloaded Frommentioning

confidence: 99%

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Saturable Uptake of Lipophilic Amine Drugs into Isolated Hepatocytes: Mechanisms and Consequences for Quantitative Clearance Prediction

Hallifax

Houston

2007

Drug Metab Dispos

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ABSTRACT:The hepatic uptake of quinine, fluvoxamine, and fluoxetine (0.1-10 M) was investigated with freshly isolated rat hepatocytes. The cell-to-medium concentration ratios (K p ) were concentration-dependent: the mean maximum K p values (at 0.1 M) were 150 (quinine), 500 (fluvoxamine), and 2000 (fluoxetine). There was also a large capacity site that was not saturable over the concentration range used (possibly partition into the phospholipid component of membranes); representing this site, the mean minimum K p values (at 10 M) were 30 (quinine), 200 (fluvoxamine), and 500 (fluoxetine). To eliminate concomitant metabolism, cells were pretreated with the irreversible P450 inhibitor, aminobenzotriazole. The saturable uptake was substantially eliminated after exposure to carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (ATP inhibitor). The difference between the maximum and minimum K p for these three amine drugs, as well as for dextromethorphan, propranolol, and imipramine, was within a limited range of 3-fold, indicating a common magnitude of saturable uptake. Basic, permeable drugs are expected to be sequestered into lysosomes, which actively maintain their low internal pH (ϳ5) using ATP, and this process is predictable from the combined effects of pH-driven ion accumulation and unsaturable binding representing partition into membranes. The resultant predicted maximum K p correlated strongly with the observed maximum K p . Thus, at low substrate concentrations, the fraction of drug unbound in the hepatocyte incubation (critical for assessing drug clearance and drug-drug interaction potential) may be dependent upon saturable as well as unsaturable binding, and for lipophilic, basic drugs, this can be readily estimated assuming a common degree of uptake into lysosomes.

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Section: Discussionmentioning

confidence: 88%

Section: Downloaded Frommentioning

confidence: 96%

Section: Downloaded Frommentioning

confidence: 99%

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Saturable Uptake of Lipophilic Amine Drugs into Isolated Hepatocytes: Mechanisms and Consequences for Quantitative Clearance Prediction

Hallifax

Houston

2007

Drug Metab Dispos

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“…Like the sulphydryl reagent N-ethylmaleimide (NEM) that inhibits, but to a different extent, both proton pump and ATPase activity of lysosomes (Dell'Antone, 1988, Arai et al, 1993, 3-Br PA too proved to only partially inhibit the latter activity. As shown in Fig.…”

Section: Studies On Isolated Rat Liver Lysosomesmentioning

confidence: 99%

Inactivation of H+-vacuolar ATPase by the energy blocker 3-bromopyruvate, a new antitumour agent

Dell’Antone

2006

Life Sciences

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“…In rat liver lysosomes, conflicting results for the effect of Ca 2+ on proton pumping have been reported and, therefore, the presence of an H+/Ca 2+ exchanger is considered uncertain. In this regard, Dell' Antone (1988) has recently reported that substitution of Ca 2+ for Mg 2 § reduced the activity of the H + ATPase by 80% but that the proton pump functioned well in the presence of both Mg 2 § and Ca 2+ suggesting the absence of an H+/Ca 2+ antiporter. On the other hand, Moriyama, Takano and Ohkuma (1984) found that CaATP did not drive the H § pump but, rather, it supported DCCD-inhibitable ATP hydrolysis suggesting Ca2+-induced uncoupling of ATP hydrolysis and H + pumping.…”

Section: Effect Of Ca 2+mentioning

confidence: 99%

H+/Ca2+ exchange in rabbit renal cortical endosomes

Hilden

Madias

1989

J. Membrain Biol.

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We have examined the effect of second messengers on ATP-driven H+ transport in an H+ ATPase-bearing endosomal fraction isolated from rabbit renal cortex. cAMP (0.1 mM) had no effect on H+ transport. Acridine orange fluorescence in the presence of 0.5 mM Ca2+ (+1 mM EGTA) was 19 +/- 6% of control. Inhibition of ATP-driven H+ transport by Ca2+ was concentration dependent; 0.25 and 0.5 mM Ca2+ (+1 mM EGTA) inhibited acridine orange fluorescence by approximately 50 and approximately 80%, respectively. Ca2+ also produced a concentration-dependent increase in the rate of pH-gradient dissipation. Ca2+ did not affect ATP hydrolysis. ATP-dependent Br- uptake was virtually unchanged in the presence of 0.5 mM Ca2+ (+1 mM EGTA). These vesicles were also shown to transport Ca2+ in an ATP-dependent mode. Inositol 1,4,5-trisphosphate had no effect on ATP-dependent Ca2+ uptake. These results are consistent with the co-existence of an H+ ATPase and an H+/Ca2+ exchanger on these endosomes, the latter transport system using the H+ gradient to energize Ca2+ uptake. Attempts to demonstrate an H+/Ca2+ antiporter in the absence of ATP have been unsuccessful. Yet, when a pH gradient was established by preincubation with ATP and residual ATP was subsequently removed by hexokinase + glucose, stimulation of Ca2+ uptake could be demonstrated. A Ca2(+)-dependent increase in H+ permeability and an ATP-dependent Ca2+ uptake might have important implications for the regulation of vacuolar H+ ATPase activity as well as the homeostasis of cytosolic Ca2+ concentration.

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Proton pump-linked Mg2+-ATPase activity in isolated rat liver lysosomes

Cited by 15 publications

References 57 publications

Saturable Uptake of Lipophilic Amine Drugs into Isolated Hepatocytes: Mechanisms and Consequences for Quantitative Clearance Prediction

Saturable Uptake of Lipophilic Amine Drugs into Isolated Hepatocytes: Mechanisms and Consequences for Quantitative Clearance Prediction

Inactivation of H+-vacuolar ATPase by the energy blocker 3-bromopyruvate, a new antitumour agent

H+/Ca2+ exchange in rabbit renal cortical endosomes

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