Acetaminophen reduces the protein levels of high affinity amino acid permeases and causes tryptophan depletion

Angelina Huseinovic, Stefan J. Dekker, Bob Boogaard, Nico P.E. Vermeulen, Jan M. Kooter, J. Chris Vos

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

In yeast, toxicity of acetaminophen (APAP), a frequently used analgesic and antipyretic drug, depends on ubiquitin-controlled processes. Previously, we showed a remarkable overlap in toxicity profiles between APAP and tyrosine, and a similarity with drugs like rapamycin and quinine, which induce degradation of the amino acid permease Tat2. Therefore, we investigated in yeast whether APAP reduced the expression levels of amino acid permeases. The protein levels of Tat2, Tat1, Mup1 and Hip1 were reduced, while the expression of the general permease Gap1 was increased, consistent with a nutrient starvation response. Overexpression of Tat1 and Tat2, but not Mup1, Hip1 and Gap1 conferred resistance to APAP. A tryptophan auxotrophic strain trp1Δ was more sensitive to APAP than wild-type and addition of tryptophan completely restored the growth restriction of trp1∆ upon APAP exposure, while tyrosine had an additive effect on APAP toxicity. Furthermore, intracellular aromatic amino acid concentrations were reduced upon APAP exposure. This effect was less prominent in ubiquitin-deficient yeast strains that were APAP resistant and showed a reduced degradation of high affinity amino acid permeases. APAP-induced changes in intracellular amino acid concentrations were also detected in hepatoma HepG2 cells indicating significance for humans.

Original languageEnglish
Pages (from-to)1377-1390
Number of pages14
JournalAmino Acids
Volume50
Issue number10
Early online date5 Jul 2018
DOIs
Publication statusPublished - Oct 2018

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Amino Acid Transport Systems
Acetaminophen
Tryptophan
Proteins
Yeast
Toxicity
Yeasts
Ubiquitin
Tyrosine
Degradation
Aromatic Amino Acids
Antipyretics
Quinine
Membrane Transport Proteins
Hep G2 Cells
Sirolimus
Starvation
Pharmaceutical Preparations
Nutrients
Analgesics

Keywords

  • Acetaminophen
  • Amino acid permeases
  • Nutrient starvation
  • Tryptophan
  • Tyrosine

Cite this

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title = "Acetaminophen reduces the protein levels of high affinity amino acid permeases and causes tryptophan depletion",
abstract = "In yeast, toxicity of acetaminophen (APAP), a frequently used analgesic and antipyretic drug, depends on ubiquitin-controlled processes. Previously, we showed a remarkable overlap in toxicity profiles between APAP and tyrosine, and a similarity with drugs like rapamycin and quinine, which induce degradation of the amino acid permease Tat2. Therefore, we investigated in yeast whether APAP reduced the expression levels of amino acid permeases. The protein levels of Tat2, Tat1, Mup1 and Hip1 were reduced, while the expression of the general permease Gap1 was increased, consistent with a nutrient starvation response. Overexpression of Tat1 and Tat2, but not Mup1, Hip1 and Gap1 conferred resistance to APAP. A tryptophan auxotrophic strain trp1Δ was more sensitive to APAP than wild-type and addition of tryptophan completely restored the growth restriction of trp1∆ upon APAP exposure, while tyrosine had an additive effect on APAP toxicity. Furthermore, intracellular aromatic amino acid concentrations were reduced upon APAP exposure. This effect was less prominent in ubiquitin-deficient yeast strains that were APAP resistant and showed a reduced degradation of high affinity amino acid permeases. APAP-induced changes in intracellular amino acid concentrations were also detected in hepatoma HepG2 cells indicating significance for humans.",
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Acetaminophen reduces the protein levels of high affinity amino acid permeases and causes tryptophan depletion. / Huseinovic, Angelina; Dekker, Stefan J.; Boogaard, Bob; Vermeulen, Nico P.E.; Kooter, Jan M.; Vos, J. Chris.

In: Amino Acids, Vol. 50, No. 10, 10.2018, p. 1377-1390.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Acetaminophen reduces the protein levels of high affinity amino acid permeases and causes tryptophan depletion

AU - Huseinovic, Angelina

AU - Dekker, Stefan J.

AU - Boogaard, Bob

AU - Vermeulen, Nico P.E.

AU - Kooter, Jan M.

AU - Vos, J. Chris

PY - 2018/10

Y1 - 2018/10

N2 - In yeast, toxicity of acetaminophen (APAP), a frequently used analgesic and antipyretic drug, depends on ubiquitin-controlled processes. Previously, we showed a remarkable overlap in toxicity profiles between APAP and tyrosine, and a similarity with drugs like rapamycin and quinine, which induce degradation of the amino acid permease Tat2. Therefore, we investigated in yeast whether APAP reduced the expression levels of amino acid permeases. The protein levels of Tat2, Tat1, Mup1 and Hip1 were reduced, while the expression of the general permease Gap1 was increased, consistent with a nutrient starvation response. Overexpression of Tat1 and Tat2, but not Mup1, Hip1 and Gap1 conferred resistance to APAP. A tryptophan auxotrophic strain trp1Δ was more sensitive to APAP than wild-type and addition of tryptophan completely restored the growth restriction of trp1∆ upon APAP exposure, while tyrosine had an additive effect on APAP toxicity. Furthermore, intracellular aromatic amino acid concentrations were reduced upon APAP exposure. This effect was less prominent in ubiquitin-deficient yeast strains that were APAP resistant and showed a reduced degradation of high affinity amino acid permeases. APAP-induced changes in intracellular amino acid concentrations were also detected in hepatoma HepG2 cells indicating significance for humans.

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