TY - JOUR
T1 - In vitro and In vivo Metabolism of the Carcinogen 4-Nitropyrene
AU - Upadhyaya, Pramod
AU - Linda, S.
AU - Tungeln, Von
AU - El-Bayoumy, Karam
PY - 1994/9/1
Y1 - 1994/9/1
N2 - The in vitro and in vivo metabolism of the potent mutagen and carcinogen, 4-nitropyrene, was studied. 4-Aminopyrene, 4-(acetylamino)pyrene, 9,10-epoxy-9,10-dihydro-4-nitropyrene, cis-and trans-9,10-dihydro-9,10-dihydroxy-4-nitropyrene, 9-and 10-hydroxy-4-nitropyrene, and 9-and 10-hydroxy-4-(acetylamino)pyrene were synthesized to serve as markers for the identification of 4-nitropyrene metabolites. Initially, 4-nitropyrene was metabolized by rat liver microsomes, or rat liver 9000g supernatant, to yield primarily two metabolites; one of these was identified as 4-nitropyrene-9,10-dione. The major metabolite of 4-nitropyrene in the presence of 3,3,3-trichloropropylene-1,2-oxide was 9,10-epoxy-9,10-dihydro-4-nitropyrene. In parallel studies, oral administration of 58 mg (0.3 mCi/mmol)/kg body weight of [3H]4-nitropyrene to female Sprague-Dawley rats, which are susceptible to mammary carcinogenesis by this agent, yielded 32% and 30.6% of the dose after 48 h as urinary and fecal excretion products, respectively. Excretion of the radioactivity remained slightly higher in the urine than in feces throughout 168 h after administration. Some of the fecal metabolites (isolated amounts expressed as % of dose) were identified as 4-aminopyrene (5.4), 9(10)-hydroxy-4-(acetylamino)pyrene (3.3), and unmetabolized 4-nitropyrene (2.4). Sulfates (3.3) and glucuronides (2.4) of 9(10)-hydroxy-4-(acetylamino)pyrene were identified in the urine. This study indicates that nitroreduction and ring oxidation are metabolic pathways of 4-nitropyrene in vivo; similar findings were obtained previously with its structural isomers 1-and 2-nitropyrene. However, the pattern of excretion of 4-nitropyrene is different; the significance of this observation in relation to tumor induction is discussed.
AB - The in vitro and in vivo metabolism of the potent mutagen and carcinogen, 4-nitropyrene, was studied. 4-Aminopyrene, 4-(acetylamino)pyrene, 9,10-epoxy-9,10-dihydro-4-nitropyrene, cis-and trans-9,10-dihydro-9,10-dihydroxy-4-nitropyrene, 9-and 10-hydroxy-4-nitropyrene, and 9-and 10-hydroxy-4-(acetylamino)pyrene were synthesized to serve as markers for the identification of 4-nitropyrene metabolites. Initially, 4-nitropyrene was metabolized by rat liver microsomes, or rat liver 9000g supernatant, to yield primarily two metabolites; one of these was identified as 4-nitropyrene-9,10-dione. The major metabolite of 4-nitropyrene in the presence of 3,3,3-trichloropropylene-1,2-oxide was 9,10-epoxy-9,10-dihydro-4-nitropyrene. In parallel studies, oral administration of 58 mg (0.3 mCi/mmol)/kg body weight of [3H]4-nitropyrene to female Sprague-Dawley rats, which are susceptible to mammary carcinogenesis by this agent, yielded 32% and 30.6% of the dose after 48 h as urinary and fecal excretion products, respectively. Excretion of the radioactivity remained slightly higher in the urine than in feces throughout 168 h after administration. Some of the fecal metabolites (isolated amounts expressed as % of dose) were identified as 4-aminopyrene (5.4), 9(10)-hydroxy-4-(acetylamino)pyrene (3.3), and unmetabolized 4-nitropyrene (2.4). Sulfates (3.3) and glucuronides (2.4) of 9(10)-hydroxy-4-(acetylamino)pyrene were identified in the urine. This study indicates that nitroreduction and ring oxidation are metabolic pathways of 4-nitropyrene in vivo; similar findings were obtained previously with its structural isomers 1-and 2-nitropyrene. However, the pattern of excretion of 4-nitropyrene is different; the significance of this observation in relation to tumor induction is discussed.
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U2 - 10.1021/tx00041a015
DO - 10.1021/tx00041a015
M3 - Article
C2 - 7841349
AN - SCOPUS:0027989557
SN - 0893-228X
VL - 7
SP - 690
EP - 695
JO - Chemical research in toxicology
JF - Chemical research in toxicology
IS - 5
ER -