In vitro and in vivo metabolism of the carcinogen 4-nitropyrene.

Abstract

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.

• Authors: P Upadhyaya, L S Von Tungeln, P P Fu, K el-Bayoumy
• Journal: Chemical research in toxicology (Chem Res Toxicol) 1994 Sep-Oct Vol. 7 Issue 5 Pg. 690-5 ISSN: 0893-228X [Print] United States
• PMID: 7841349 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Pyrenes
• 4-nitropyrene

Topics

• Animals
• Biotransformation
• Carcinogens (chemical synthesis, metabolism, pharmacokinetics)
• Chromatography, High Pressure Liquid
• Feces (chemistry)
• Female
• In Vitro Techniques
• Male
• Microsomes, Liver (metabolism)
• Oxidation-Reduction
• Pilot Projects
• Pyrenes (chemical synthesis, metabolism, pharmacokinetics)
• Rats
• Rats, Sprague-Dawley
• Spectrophotometry, Ultraviolet