Effect of aryl hydrocarbon hydroxylase induction on the in vivo covalent binding of 1-nitropyrene, benzo[a]pyrene, 2-aminoanthracene, and phenanthridone to mouse lung deoxyribonucleic acid

The effect of aryl hydrocarbon hydroxylase induction on the covalent binding of 1-nitropyrene (1-NP), benzoa]pyrene (BaP), 2-aminoanthracene (2-AA), and phenanthridone (PNDO) to mouse lung DNA was investigated. Cytochrome P-450-dependent monooxygenases were induced in mouse lung by intratracheal instillation of BaP, Aroclor-1254, or coal gas condensate (CGC) 24 hr before instillation of 3H]BaP, 3H]-2-AA, 14C]-1-NP, or 14C]PNDO. All inducing agents increased the amount of radioactivity of 3H]BaP, 3H]-2-AA, and 14C]-1-NP or metabolites bound to DNA. However, pretreatment with BaP resulted in the highest amounts of radiolabels covalently bound to DNA. At 4 hr after instillation of radiolabels in BaP-induced mice, the amounts of 3H]BaP, 3H]-2-AA, and 14C]-1-NP bound to DNA were increased 5.4-, 5.2-, and 160-fold above that of control levels; the amount of 1-NP bound to DNA was fifty times higher than the amount bound by BaP. Labeled compounds were still bound to DNA 1 week after administration. 14C]PNDO was not bound to DNA in uninduced or induced mice. Based on the amount of labeled compounds bound to DNA, pretreatment of mice with BaP and CGC induced enzymes with similar specificities; however, enzymes induced by Aroclor were less effective in the metabolism of labeled compounds to DNA-bound products. These data show that specific cytochrome P-450-dependent monooxygenases are inducible in mouse lung and suggest that pre-exposure to inducing agents may be important in the potential toxicity to proximal tissues in direct contact with inhaled xenobiotics.