Abstract
Previous studies have shown that cytochrome P-450-mediated metabolism of naphthalene results in dose-dependent bronchiolar necrosis in mice and in the formation of reactive metabolites which deplete reduced glutathione and become bound covalently to tissue macromolecules. The finding that pulmonary glutathione levels were nearly totally depleted after large doses of naphthalene suggested that hepatic formation of reactive metabolites may contribute substantially to glutathione depletion and covalent binding in extrahepatic tissues. This possibility has been supported by several new lines of evidence: 1) similar levels of covalent binding were observed in lung, liver and kidney in vivo, yet the rate of kidney microsomal metabolic activation of naphthalene was much lower than in liver or lung; 2) phenobarbital pretreatment markedly increased in vivo covalent binding in lung, liver and kidney and increased hepatic but decreased pulmonary microsomal covalent binding; 3) 3-methylcholanthrene pretreatment resulted in slightly increased levels of covalent binding in lung, liver and kidney yet decreased pulmonary microsomal covalent binding; 4) administration of p-xylene, at doses which selectively decreased pulmonary microsomal metabolism of biphenyl (4-hydroxylation) and naphthalene (to reactive metabolites), decreased in vivo covalent binding in liver and kidney to the same extent as lung after [14C]naphthalene; and 5) pretreatment with buthionine sulfoximine preferentially depleted hepatic and renal but not pulmonary glutathione levels and markedly increased covalent binding in all three tissues. The severity of naphthalene-induced bronchiolar damage was unaffected by pretreatment with phenobarbital, 3-methylcholanthrene or p-xylene but was increased by prior administration of buthionine sulfoximine. These studies suggest that a portion of the reactive metabolites which deplete glutathione and bind covalently in extrahepatic tissues originate in the liver. Whether these circulating metabolites play a role in naphthalene-induced pulmonary bronchiolar damage is not clear.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8-16 |
| Number of pages | 9 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 225 |
| Issue number | 1 |
| State | Published - 1983 |
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ASJC Scopus subject areas
- Pharmacology
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Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extrahepatic tissues in vivo. / Buckpitt, Alan R; Warren, D. L.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 225, No. 1, 1983, p. 8-16.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extrahepatic tissues in vivo
AU - Buckpitt, Alan R
AU - Warren, D. L.
PY - 1983
Y1 - 1983
N2 - Previous studies have shown that cytochrome P-450-mediated metabolism of naphthalene results in dose-dependent bronchiolar necrosis in mice and in the formation of reactive metabolites which deplete reduced glutathione and become bound covalently to tissue macromolecules. The finding that pulmonary glutathione levels were nearly totally depleted after large doses of naphthalene suggested that hepatic formation of reactive metabolites may contribute substantially to glutathione depletion and covalent binding in extrahepatic tissues. This possibility has been supported by several new lines of evidence: 1) similar levels of covalent binding were observed in lung, liver and kidney in vivo, yet the rate of kidney microsomal metabolic activation of naphthalene was much lower than in liver or lung; 2) phenobarbital pretreatment markedly increased in vivo covalent binding in lung, liver and kidney and increased hepatic but decreased pulmonary microsomal covalent binding; 3) 3-methylcholanthrene pretreatment resulted in slightly increased levels of covalent binding in lung, liver and kidney yet decreased pulmonary microsomal covalent binding; 4) administration of p-xylene, at doses which selectively decreased pulmonary microsomal metabolism of biphenyl (4-hydroxylation) and naphthalene (to reactive metabolites), decreased in vivo covalent binding in liver and kidney to the same extent as lung after [14C]naphthalene; and 5) pretreatment with buthionine sulfoximine preferentially depleted hepatic and renal but not pulmonary glutathione levels and markedly increased covalent binding in all three tissues. The severity of naphthalene-induced bronchiolar damage was unaffected by pretreatment with phenobarbital, 3-methylcholanthrene or p-xylene but was increased by prior administration of buthionine sulfoximine. These studies suggest that a portion of the reactive metabolites which deplete glutathione and bind covalently in extrahepatic tissues originate in the liver. Whether these circulating metabolites play a role in naphthalene-induced pulmonary bronchiolar damage is not clear.
AB - Previous studies have shown that cytochrome P-450-mediated metabolism of naphthalene results in dose-dependent bronchiolar necrosis in mice and in the formation of reactive metabolites which deplete reduced glutathione and become bound covalently to tissue macromolecules. The finding that pulmonary glutathione levels were nearly totally depleted after large doses of naphthalene suggested that hepatic formation of reactive metabolites may contribute substantially to glutathione depletion and covalent binding in extrahepatic tissues. This possibility has been supported by several new lines of evidence: 1) similar levels of covalent binding were observed in lung, liver and kidney in vivo, yet the rate of kidney microsomal metabolic activation of naphthalene was much lower than in liver or lung; 2) phenobarbital pretreatment markedly increased in vivo covalent binding in lung, liver and kidney and increased hepatic but decreased pulmonary microsomal covalent binding; 3) 3-methylcholanthrene pretreatment resulted in slightly increased levels of covalent binding in lung, liver and kidney yet decreased pulmonary microsomal covalent binding; 4) administration of p-xylene, at doses which selectively decreased pulmonary microsomal metabolism of biphenyl (4-hydroxylation) and naphthalene (to reactive metabolites), decreased in vivo covalent binding in liver and kidney to the same extent as lung after [14C]naphthalene; and 5) pretreatment with buthionine sulfoximine preferentially depleted hepatic and renal but not pulmonary glutathione levels and markedly increased covalent binding in all three tissues. The severity of naphthalene-induced bronchiolar damage was unaffected by pretreatment with phenobarbital, 3-methylcholanthrene or p-xylene but was increased by prior administration of buthionine sulfoximine. These studies suggest that a portion of the reactive metabolites which deplete glutathione and bind covalently in extrahepatic tissues originate in the liver. Whether these circulating metabolites play a role in naphthalene-induced pulmonary bronchiolar damage is not clear.
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M3 - Article
C2 - 6834280
AN - SCOPUS:0020632392
VL - 225
SP - 8
EP - 16
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 1
ER -