After transplacental exposure of patas and rhesus monkeys to N- nitrosoethylurea, 10-40% of the offspring developed infiltrating angiolipoma of skeletal muscle, a lesion identical to that seen in the human. The lesions typically arose within infiltrated and displaced skeletal muscle, most commonly in the lower extremities. Though they did not metastasize, they did recur if incompletely resected. The great clinical and morphological similarity of this condition to that observed in humans suggests that it may likewise be caused by exposure to an agent during human pregnancy. The metabolism of the tobacco-specific nitrosamine 4-(methyl-amino)-1-(3-pyridyl)-1-butanone (NKK) was examined in the patas monkey in order to provide further information about NNK metabolic pathways in primates. Metabolism by alpha-hydroxylation of NNK was rapid and extensive, and the products of this pathway 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. NNK was also metabolized by carbonyl reduction to the butanol (NNAL), which was excreted in part as diasteromeric O-glucuronides. The more prevalent of the two glucuronides had not been observed in studies with NNK in rodents. It was characterized by its spectral properties, by enzymatic hydrolysis, and by derivatization of the released NNAL enantiomer. This glucuronide was subsequently detected in human urine. The pharmacokinetic parameters in the patas were consistent with those observed in previous studies of nitrosamines, and varied predictably with body weight in five species. The results of this study have provided new insights relevant to assessing human metabolism of NNK.
NIH ExPorter
NIH ExPorter