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 glutathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degrees C in cytosol and microsomes of liver and lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfactory nasal mucosa of F344 rats. In all of these tissues, GST and EH activities were detected. GST activity for PO was found in cytosolic fractions exclusively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, representing 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)) could be quantified for all tissues. In liver and lung, these ratios ranged from 12 (human liver) to 106 microl/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 highest 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 alike in both rat tissues. Species-specific EH activities in lung were similar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver.
Faller
T H
TH
GSF-Institut für Toxikologie, Neuherberg, Germany.
Csanády
G A
GA
Kreuzer
P E
PE
Baur
C M
CM
Filser
J G
JG
D000818:Animals; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D004852:Epoxy Compounds; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C009068:propylene oxide