Biological fate of [C-14]-l-nitropyrene in rats following intragastric administration

1-Nitropyrene (1-NP), a weak carcinogen associated with diesel exhaust part icles, has previously been detected in workplace atmospheres with in-use di esel engines and in the general environment. In order to gain insight in it s biological fate, a single dose of [C-14]-1-NP (27.6 mu Ci, 750 mg/kg body weight, b.w.) was administered intragastrically to rats and the presence o f metabolites in blood and tissue homogenates, and radioactivity associated with blood proteins and tissue DNA, were studied. Early peak levels of rad ioactivity observed in blood and tissue homogenates indicated a rapid absor ption of [C-14]-1-NP from the gastrointestinal tract. Metabolite patterns o bserved in plasma, liver and kidney homogenates strongly suggested an impor tant role of the intestinal microflora in the enterohepatic recirculation, but not in nitroreduction of 1-NP prior to ribsorption from the gastrointes tinal tract. This might explain the low levels of radioactivity associated with blood proteins, since 1-nitrosopyrene, a product of nitroreduction of 1-NP, is likely to be involved in protein binding. Levels of radioactivity associated with plasma proteins were approximately four times higher than t he levels of radioactivity associated with hemoglobin (401.0 and 84.1 pmol/ g protein per mu mol 1-NP kg b.w., respectively, at 24 h). Maximal 25% of t he associated radioactivity was released following mild alkaline hydrolysis of either hemoglobin or plasma proteins. 1-Aminopyrene was the only releas ed compound after hydrolysis of hemoglobin. In addition to 1-aminopyrene, t wo more polar unidentified metabolites were defected following hydrolysis o f plasma proteins. Association of radioactivity with DNA was highest in the liver at the first moments of observation (7.4 pmol C-14 Eq./mg DNA per mu mol 1-NP kg b.w.), but decreased rapidly to levels lower than observed for kidney DNA (max. 3.0 pmol C-14 Eq./mg DNA per mu mol 1-NP kg b.w. at 24 h) . In lungs 8-50 times less radioactivity was associated with DNA than obser ved in the liver and kidneys. The results of this study show, that 1-NP und ergoes an extensive and complex biotransformation in vivo, resulting in a v ariety of metabolites present in blood and tissue homogenates and a diversi ty of blood protein adducts. Concentrations of plasma metabolites, blood pr otein adducts and DNA adducts were rather low. In addition, previous studie s also showed relatively low concentrations of metabolites present in urine . Therefore, sensitive and selective methods will be needed in order to eva luate the biological fate of 1-NP, associated with diesel exhaust particles , in humans. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.