Microsomal N-glucuronidation of nicotine and cotinine: human hepatic interindividual, human intertissue, and interspecies hepatic variation.
Two of the abundant conjugates of human nicotine metabolism result from the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, transformations we recently demonstrated in liver microsomes. We further studied these microsomal N-glucuronidation reactions with respect to human hepatic interindividual, human intertissue, and interspecies hepatic variation. The reactivities of microsomes from human liver (n = 12), various human tissues, and liver from eight species toward the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, and also R-(+)-nicotine in human liver were examined. Assays with (14)C-labeled substrates involved radiometric high-performance liquid chromatography. For the human liver samples examined there were 13- to 17-fold variations in the catalytic activities observed toward S-(-)-nicotine, R-(+)-nicotine, and S-(-)-cotinine. Gender and smoking effects were studied, and after exclusion of an outlier a decrease in catalytic activity in females was observed. Significant correlations were observed between all three analytes, indicating that the same UDP-glucuronosyltransferase(s) enzyme is likely to be involved in these transformations. Catalytic activities were not observed for human gastrointestinal tract (colon, duodenum, ileum, jejunum, and stomach), kidney, or lung microsomes. For the seven animal species examined, activity was measurable only for monkey, guinea pig, and minipig, and only for S-(-)-nicotine N-glucuronidation and at rates 10- to 40-fold lower than humans. Activity was not measurable in the case of dog, mouse, rabbit, or rat, for the latter under five different treatment conditions for one of the strains. In conclusion, there are large hepatic interindividual variations in N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, in human extrahepatic metabolism seems limited, and none of the animal strains examined resembled human.
Ghosheh
Omar
O
Drug Metabolism and Drug Disposition Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Hawes
Edward M
EM
D000818:Animals; D003367:Cotinine / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009538:Nicotine / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012907:Smoking / Q000378:metabolism; D013045:Species Specificity; D013556:Swine, Miniature; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*
D014535:Uridine Diphosphate Glucuronic Acid; D009538:Nicotine; D003367:Cotinine