API

Relationship: 886

Title

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Decrease, Intracellular pH leads to Increase, Cytotoxicity

Upstream event

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Decrease, Intracellular pH

Downstream event

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Increase, Cytotoxicity

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors adjacent Moderate High

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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pH reduction results in protonation of cellular macromolecules (e.g. proteins, lipids, enzymes, transporters, RNA), leading to disruption of function, eventually leading to loss of cellular homeostasis and cell death.

Evidence Supporting this KER

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Biological Plausibility

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Cellular pH is regulated in a narrow range by intracellular buffers, and proton pumps[1]. It is highly plausible that reductions in cellular pH would become cytotoxic as disruption of the normal structure and function of cellular macromolecules increases.

Empirical Evidence

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Support for this linkage comes from the general literature and direct evidence from in vitro systems. Acetic acid, but not acetaldehyde was shown to be cytotoxic to respiratory tissue explants in vitro. Metabolism of vinyl acetate, which produces protons, induces significant intracellular pH reduction and is cytotoxic, is further experimental evidence of a linkage between pH reduction and toxicity[2]. Reductions in cellular pH exceeding homeostatic controls is reported to lead to denatured/dysfunctional cellular apparatus (enzymes)[3] and cell death[4].


Uncertainties and Inconsistencies

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None identified.

Quantitative Understanding of the Linkage

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The quantitative understanding supporting a linkage between pH reduction and cytotoxicity includes dose-response data showing pH reduction in several in vitro systems and dose-response data showing cytotoxicity data in several in vitro systems. Estimates of pH reductions associated with cytotoxic exposures to one chemical initiator, vinyl acetate, were made using biokinetic models[5].

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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General: pH regulation is necessary for all biological systems. Disruption of cellular macromolecules with reduced pH is a physicochemical effect applicable to all biological systems.

References

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  1. Izumi, Torigoe, Ishiguchi, Uramoto, Yoshida, Tanabe, Ise, Murakami, Yoshida, Nomoto and Kohno (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 29: 541-549
  2. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431, Budinsky, Gollapudi, Albertini, Valentine, Stavanja, Teeguarden, Fensterheim, Rick, Lardie, McFadden, Green and Recio (2013). Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells. Environ Mol Mutagen. 54: 755-768
  3. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326
  4. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Izumi, Torigoe, Ishiguchi, Uramoto, Yoshida, Tanabe, Ise, Murakami, Yoshida, Nomoto and Kohno (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 29: 541-549, Fais (2010). Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 267: 515-525
  5. Plowchalk, Andersen and Bogdanffy (1997). Physiologically Based Modeling of Vinyl Acetate Uptake, Metabolism, and Intracellular pH Changes in the Rat Nasal Cavity. Toxicology and Applied Pharmacology. 142: 386-400