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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.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2011 Apr; Vol. 79 (4), pp. 710-23. Date of Electronic Publication: 2011 Jan 20. - Publication Year :
- 2011
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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.
- Subjects :
- Acetaminophen pharmacokinetics
Animals
Biological Availability
Cytochrome P-450 CYP2A6
Cytochrome P450 Family 2
Gene Expression Regulation drug effects
Gene Expression Regulation physiology
Homeostasis drug effects
Homeostasis physiology
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Nasal Mucosa drug effects
Nasal Mucosa enzymology
Acetaminophen toxicity
Androgen-Binding Protein biosynthesis
Aryl Hydrocarbon Hydroxylases physiology
Nasal Mucosa metabolism
Salivary Proteins and Peptides biosynthesis
Testosterone physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 79
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21252290
- Full Text :
- https://doi.org/10.1124/mol.110.070045