Kinetics of propylene oxide metabolism in microsomes and cytosol of different organs from mouse, rat, and humans

Kinetics of the metabolic inactivation of 1,2-epoxypropane (propylene oxide ; PO) catalyzed by gluathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degreesC in cytosol and microsomes of liver an d lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfacto ry nasal mucosa of F344 rats. In all of these tissues, GST and EH activitie s were detected. GST activity for PO was found in cytosolic fractions exclu sively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, rep resenting 1-3% of the corresponding GST activity. For GST, the ratio of the maximum metabolic rate (V-max) to the apparent Michaelis constant (K-m) co uld be quantified for all tissues. In liver and lung, these ratios ranged f rom 12 (human liver) to 106 mul/min/mg protein (mouse lung). Corresponding values for EH ranged from 4.4 (mouse liver) to 46 (human lung). The lowest V-max value for EH was found in mouse lung (7.1 nmol/min/mg protein); the h ighest was found in human liver (80 nmol/min/mg protein). K-m values for EH -mediated PO hydrolysis in liver and lung ranged from 0.83 (human lung) to 3.7 mmol/L (mouse liver). With respect to liver and lung, the highest V-max /K-m ratios were obtained for GST in mouse and for EH in human tissues. GST activities were higher in lung than in liver of mouse and human and were a like in both rat tissues. Species-specific EH activities in lung were simil ar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver, (C) 2001 Academic Press.