Upadhyaya P, Von Tungeln L S, Fu P P, el-Bayoumy K
American Health Foundation, Valhalla, New York 10595.
Chem Res Toxicol. 1994 Sep-Oct;7(5):690-5. doi: 10.1021/tx00041a015.
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.
对强效诱变剂和致癌物4-硝基芘的体内外代谢进行了研究。合成了4-氨基芘、4-（乙酰氨基）芘、9,10-环氧-9,10-二氢-4-硝基芘、顺式和反式-9,10-二氢-9,10-二羟基-4-硝基芘、9-和10-羟基-4-硝基芘以及9-和10-羟基-4-（乙酰氨基）芘，用作鉴定4-硝基芘代谢物的标志物。最初，4-硝基芘经大鼠肝微粒体或大鼠肝9000g上清液代谢，主要产生两种代谢物；其中一种被鉴定为4-硝基芘-9,10-二酮。在3,3,3-三氯丙烯-1,2-氧化物存在下，4-硝基芘的主要代谢物是9,10-环氧-9,10-二氢-4-硝基芘。在平行研究中，给易受该致癌物诱发乳腺癌的雌性Sprague-Dawley大鼠口服58mg（0.3mCi/mmol）/kg体重的[3H]4-硝基芘，48小时后，分别有32%和30.6%的剂量以尿液和粪便排泄产物的形式排出。给药后168小时内，尿液中的放射性排泄量始终略高于粪便。一些粪便代谢物（分离量以剂量的百分比表示）被鉴定为4-氨基芘（5.4）、9（10）-羟基-4-（乙酰氨基）芘（3.3）和未代谢的4-硝基芘（2.4）。尿液中鉴定出9（10）-羟基-4-（乙酰氨基）芘的硫酸盐（3.3）和葡萄糖醛酸苷（2.4）。本研究表明，硝基还原和环氧化是4-硝基芘在体内的代谢途径；先前对其结构异构体1-硝基芘和2-硝基芘的研究也有类似发现。然而，4-硝基芘的排泄模式不同；讨论了这一观察结果与肿瘤诱导的关系。
