1-Nitronaphthalene toxicity in rat lung and liver: effects of inhibiting and inducing cytochrome P450 activity.
In rats, 1-nitronaphthalene (1-NN) causes both pulmonary and hepatic toxicity. Pulmonary toxicity is evident as bronchiolar damage, with necrosis of Clara cells and ciliated cells, whereas hepatic injury involves vacuolation of centrilobular hepatocytes. Pretreatment with O,O,S-trimethylphosphorodithioate [OOS-MeP(S)] or p-xylene gave three- to fourfold protection against 1-NN toxicity. These pretreatments also prevented both the increase in lung weight and the rise in gamma-glutamyltranspeptidase and alkaline phosphatase activity in bronchoalveolar lavage fluid normally associated with 1-NN toxicity. Pretreatment with Aroclor 1254 or beta-naphthoflavone (beta-NF) did not alter the LD50 of 1-NN. Aroclor or beta-NF pretreatment did, however, prevent morphological signs of lung injury and any increase in either lung weight or enzyme activity in bronchoalveolar lavage fluid. Liver damage was not prevented by these treatments; indeed, injury was exacerbated and was transferred from centrilobular to periportal areas. In control rats the covalent binding of [1-14C]NN to liver microsomes was eight times greater than to lung microsomes. Pretreatment with OOS-MeP(S) decreased covalent binding to lung microsomes, without affecting binding to liver microsomes. Conversely, both Aroclor and beta-NF slightly increased covalent binding in lung, but increased liver binding by 250-300%. Phenobarbitone also increased binding to liver microsomes by 250-300%, but failed to increase, or alter, the distribution of liver damage. The reported effects of these pretreatments indicate that the toxicity of 1-NN is probably activated by isoenzyme CYP2B1 in lung, but by isoenzymes CYP1A1 or CYP1A2 in the liver.
Verschoyle
R D
RD
MRC Toxicology Unit, Carshalton, Surrey, United Kingdom.
Carthew
P
P
Wolf
C R
CR
Dinsdale
D
D
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D020111:Chlorodiphenyl (54% Chlorine); D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007928:Lethal Dose 50; D008171:Lung Diseases / Q000139:chemically induced*; D008861:Microsomes / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism* / Q000633:toxicity*; D063086:Organothiophosphates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014992:Xylenes / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001140:Aroclors; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009281:Naphthalenes; D063086:Organothiophosphates; D014992:Xylenes; D020111:Chlorodiphenyl (54% Chlorine); C065349:O,O,S-trimethylphosphorodithionate; D019324:beta-Naphthoflavone; C031286:4-xylene; C100092:bromophos; D003577:Cytochrome P-450 Enzyme System; C016614:1-nitronaphthalene