RESUMO
In vitro rates of deacetylation were measured with carcinogenic and noncarcinogenic isomeric arylamides using microsomal preparations from guinea pig, hamster, rat, mouse, rabbit and dog. Following incubation at 37 degrees, the substrate and hydrolysis products were extracted into ether and the corresponding aromatic amine quantified by gas-liquid chromatography. The data show that rates of deacetylation were both species and isomer dependent. In general, the highest rate of deacetylation in microsomes from all species was recorded with 2-acetamidobiphenyl (2-AABP); however, the mouse uniquely deacetylated 4-acetamidobiphenyl (4-AABP) most rapidly. The meta isomer 3-acetamidobiphenyl (3-AABP) was deacetylated at an intermediate rate in all species investigated. The variability in the rates of deacetylation within species may reflect the heterogeneity of the deacetylase enzymes and may be an important factor in amine/amide carcinogenesis.
Assuntos
Compostos de Aminobifenil/metabolismo , Microssomos Hepáticos/metabolismo , Animais , Cricetinae , Cães , Feminino , Cobaias , Isomerismo , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/efeitos dos fármacos , Paraoxon/farmacologia , Proadifeno/farmacologia , Coelhos , Ratos , Ratos Endogâmicos , Fluoreto de Sódio/farmacologia , Especificidade da EspécieRESUMO
Recently, the detection of urinary glucuronide conjugates of nicotine and its two major metabolites, trans-3'-hydroxycotinine and cotinine, showed that glucuronidation is an important pathway of nicotine metabolism in humans. (S)-(-)-Nicotine-N(+)-1-beta-glucuronide (quaternary N-glucuronide with linkage through the pyridino-nitrogen of nicotine) was shown to be an important nicotine metabolite of humans in vivo. The present study was undertaken to develop an animal model for this process, in order to ascertain the factors influencing quaternary N-glucuronide formation. (S)-(-)-Nicotine-N(+)-1-beta-glucuronide was formed in vitro when [2'-14C]-nicotine was incubated with Triton X-100 activated marmoset hepatic microsomes in the presence of uridine diphosphoglucuronic acid; it was not formed when activated microsomal preparations of rabbit, guinea-pig, or rat were used as enzyme source. The glucuronide was characterised by comparison with authentic synthetic (S)-(-)-nicotine-N(+)-1-beta-glucuronide using HPLC. The rate of formation of the glucuronide was almost linear during up to four hours of incubation, but still only accounted for a maximum of 6.0% of the available substrate at the end of five hours incubation. The synthetic and biosynthetic (S)-(-)-nicotine-N(+)-1-beta-glucuronides were hydrolysed by beta-glucuronidase and alkali, but were resistant to acid hydrolysis. The results support the concept that the marmoset may be a good animal species to mimic man in studies of nicotine metabolism during exposure to tobacco smoke. In vitro studies using (+/-)-trans-3'-hydroxycotinine or (S)-(-)-cotinine (as potential substrate) and [14C]-uridine diphospho-glucuronic acid (as cofactor) failed to produce any new radiolabelled glucuronide when the above microsomal preparations were used.