Abstract
CYP2G1 is a cytochrome P450 monooxygenase expressed uniquely in the olfactory mucosa (OM). We have generated Cyp2g1-null mice to identify the roles of CYP2G1 in the biology and the tissue-specific toxicity of xenobiotic compounds in the nose. Homozygous Cyp2g1-null mice are viable and fertile; they show no evidence of embryonic lethality, morphological abnormality, or developmental deficits; and they seem to have normal olfactory ability. However, OM microsomes from Cyp2g1-null mice were found to have significantly lower activities than microsomes from wild-type mice in the metabolism of testosterone and progesterone (∼60% decrease) and in the metabolic activation of coumarin (>70% decrease). Unexpectedly, a significant reduction in the expression of the Cyp2a5 gene was found in the liver, the lateral nasal gland (LNG), and, to a lesser extent, the kidney of adult Cyp2g1-null mice. The loss of CYP2G1 expression, and the associated decrease in the hepatic expression of CYP2A5, did not decrease systemic clearance, extent of hepatotoxicity, or OM toxicity of acetaminophen (AP). However, the LNG was protected from AP (at 400 mg/kg) toxicity in the Cyp2g1-null mice. Paradoxically, the LNG did not have detectable CYP2G1, and the decrease in LNG CYP2A5 expression in the Cyp2g1-null mice was not accompanied by decreases in microsomal AP metabolism. We hypothesize that OM CYP2G1 (through a paracrine pathway) or LNG CYP2A5 may indirectly influence resistance of the LNG to chemical toxicity, possibly by regulating gene expression in the LNG through steroid hormones or other endogenous P450 substrates and their metabolites.
Footnotes
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This work was supported in part by Public Health Service grant ES07462 from the National Institute of Environmental Health Sciences, National Institutes of Health.
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DOI: 10.1124/jpet.103.060301.
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ABBREVIATIONS: OM, olfactory mucosa; DCBN, 2,6-dichlorobenzonitrile; P450, cytochrome P450; BAC, bacterial artificial chromosome; AP, acetaminophen; LNG, lateral nasal gland; PEG, polyethylene glycol; ALT, alanine aminotransferase; o-HPA, o-hydroxyphenylacetaldehyde; kb, kilobase pair; bp, base pair; CPR, NADPH-cytochrome P450 reductase; PCR, polymerase chain reaction.
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↵1 Current address: Cancer Pharmacology, 841 BRB II/III, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104-6160.
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↵2 Current address: Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503.
- Received September 18, 2003.
- Accepted November 5, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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