| Autor: |
Hecht, Stephen S., Trushin, Neil, Reid-Quinn, Cheri A., Burak, Eric S., Jones, Ann Butler, Southers, Janice L., Gombar, Charles T., Carmella, Steven G., Anderson, Lucy M., Rice, Jerry M. |
| Zdroj: |
Carcinogenesis; 1993, Vol. 14 Issue 2, p229-236, 8p |
| Abstrakt: |
The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in the patas monkey, in order to provide further information about NNK metabolic pathways in primates. Female patas monkeys were given i. v. injections of [5-H]NNK, and metabolites in serum and urine were analyzed by HPLC. Metabolism by α-hydroxylation of NNK was rapid and extensive, and the products of this pathway, 4-hydroxy-4-(3-pyridyl)butyric acid and 4-oxo-4-(3-pyridyl) butyric acid, accounted for a relatively large proportion of serum and urinary metabolites at all time points. This is significant because the formation of these products is associated with modification of DNA by NNK. The other major metabolic pathway was carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which detected both unconjugated and diastereomeric Oglucuronides. One of these glucuronides had been previously identified in rat urine, but the other diastereomer, which was the more prevalent of the two in serum and urine, had not been observed in studies of NNK metabolism in rodents. It was characterized by its spectral properties, by enzymatic hydrolysis to NNAL, and by derivatization of the released NNAL enantiomer with (R)-(+)-α-methylbenzylisocyanate. The two NNAL glucuronides accounted for 15–20% of the urinary metabolites in monkeys given 0.1μg/kg NNK, which is similar to a smoker's dose, suggesting their use as dosimeters of NNK exposure in humans. Pharmacokinetic parameters were consistent with those observed in previous studies of nitrosamines, and varied predictably with body weight of five species. The results of this study have provided new insights relevant to assessing human metabolism of NNK. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
