Event:867

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Event Title

Intracellular pH, Decrease
Intracellular pH, Decrease

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors MIE Strong

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

  1. Vinyl acetate
  2. Ethyl acetate
  3. Propyl Acetate

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. ABTC 42503 Rattus sp. ABTC 42503 Strong NCBI
mouse Mus musculus Strong NCBI
human Homo sapiens Moderate NCBI

Level of Biological Organization

Biological Organization
Cellular

How this Key Event works

Cells regulate proton concentrations within a narrow range with intracellular buffers and plasma membrane-bound transportors such as the Na+/H+ antiportor, and others such as the vacuolar proton pump[1]. Increased production or reduced buffering of protons can exceed homeostatic control mechanisms and cause intracellular acidification.

How it is Measured or Detected

Intracellular pH can be measured in vitro using membrane permeable pH sensitive dyes, [2] and in vivo using ratiometric NIR fluorescent probes[3]. pH change can be measured using pH sensitive dyes distributed to the intracellular space, as was done in liver cells and nasal tissue and oral cavity epithelia[4].

Evidence Supporting Taxonomic Applicability

All cells regulate intracellular pH and produce protons as a normal byproduct of metabolism.

Evidence for Chemical Initiation of this Molecular Initiating Event

Production of protons from metabolism of vinyl acetate, for example, has been shown to reversibly acidify cells in culture [5], and nasal/buccal tissue explants[6]. Cleavage of any acetate ester will produce acetic acid, increases cellular proton loading. For example, [Q from Bogdanffy Tox Letters 2003] vinyl acetate is hydrolyzed to acetic acid and vinyl alcohol, which readily rearranges to acetaldehyde. This conversion has been shown to be dependent on carboxylesterase and is catalyzed by extracts of nasal respiratory and olfactory tissue, oral cavity mucosa, lung and liver [7]. Other related acetate esters, for example ethyl acetate, butyl acetate, and propyl acetate would produce protons upon ester cleavage by releasing acetic acid.

References

  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, Nakamoto, Wagner, Melvin and Bogdanffy (2005). Vinyl acetate induces intracellular acidification in mouse oral buccal epithelial cells. Toxicol Lett. 158: 116-121
  3. Li, Wang, Yang, Zhao, Yuan, Zheng and Yang (2015). Hemicyanine-based high resolution ratiometric near-infrared fluorescent probe for monitoring pH changes in vivo. Anal Chem. 87: 2495-2503
  4. 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, Nakamoto, Wagner, Melvin and Bogdanffy (2005). Vinyl acetate induces intracellular acidification in mouse oral buccal epithelial cells. Toxicol Lett. 158: 116-121
  5. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326
  6. Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431, Nakamoto, Wagner, Melvin and Bogdanffy (2005). Vinyl acetate induces intracellular acidification in mouse oral buccal epithelial cells. Toxicol Lett. 158: 116-121
  7. Simon, Filser and Bolt (1985). Metabolism and pharmacokinetics of vinyl acetate. Arch Toxicol. 57: 191-195, Bogdanffy and Taylor (1993). Kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate. Drug Metabolism and Disposition. 21: 1107-1111, Bogdanffy, Sarangapani, Kimbell, Frame and Plowchalk (1998). Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique. Toxicological Sciences. 46: 235-246, Bogdanffy, Manning and Sarangapani (1999). High-affinity nasal extraction of vinyl acetate vapor is carboxylesterase dependent. Inhal Toxicol. 11: 927-941, Morris, Symanowicz and Sarangapani (2002). Regional distribution and kinetics of vinyl acetate hydrolysis in the oral cavity of the rat and mouse. Toxicol Lett. 126: 31-39