A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland: role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression

Xin Zhou, Yuan Wei, Fang Xie, Christina M Laukaitis, Robert C. Karn, Kerri Kluetzman, Jun Gu, Qing Yu Zhang, Dean W. Roberts, Xinxin Ding

Research output: Contribution to journalArticle

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Abstract

To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild-type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP-treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.

Original languageEnglish (US)
Pages (from-to)710-723
Number of pages14
JournalMolecular Pharmacology
Volume79
Issue number4
DOIs
StatePublished - Apr 2011

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Androgen-Binding Protein
Acetaminophen
Nose
Testosterone
Homeostasis

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland : role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression. / Zhou, Xin; Wei, Yuan; Xie, Fang; Laukaitis, Christina M; Karn, Robert C.; Kluetzman, Kerri; Gu, Jun; Zhang, Qing Yu; Roberts, Dean W.; Ding, Xinxin.

In: Molecular Pharmacology, Vol. 79, No. 4, 04.2011, p. 710-723.

Research output: Contribution to journalArticle

Zhou, Xin ; Wei, Yuan ; Xie, Fang ; Laukaitis, Christina M ; Karn, Robert C. ; Kluetzman, Kerri ; Gu, Jun ; Zhang, Qing Yu ; Roberts, Dean W. ; Ding, Xinxin. / A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland : role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression. In: Molecular Pharmacology. 2011 ; Vol. 79, No. 4. pp. 710-723.
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abstract = "To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild-type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP-treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.",
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