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.

Toxicokinetics of inhaled propylene in mouse, rat, and human.

A physiological toxicokinetic (PT) model was developed for inhaled propylene gas (PE) in mouse, rat, and human. Metabolism was simulated to occur in the liver (90%) and in the richly perfused tissue group (10%). The partition coefficients tissue:air were determined in vitro using tissues of mice, rats, and humans. Most of the tissues have partition coefficients of around 0.5. Only adipose tissue displays a 10 times higher value. The partition coefficient blood:air in human is 0.44, about half of that in rodents. PE can accumulate in the organism only barely. For male B6C3F1 mice and male Fischer 344/N rats, parameters of PE metabolism were obtained from gas uptake experiments. Maximum rates of metabolism (V(maxmo)) were 110 micromol/h/kg in mice and 50.4 micromol/h/kg in rats. V(maxmo)/2 was reached in mice at 270 ppm and in rats at 400 ppm of atmospheric PE. Pretreatment of the animals with sodium diethyldithiocarbamate resulted in an almost complete inhibition of PE metabolism in both species. Preliminary toxicokinetic data on PE metabolism in humans were obtained in one volunteer who was exposed up to 4.5 h to constant concentrations of 5 and 25 ppm PE. The PT model was used to calculate PE blood concentrations at steady state. At 25 ppm, the blood values were comparable across species, with 0.19, 0.32, and 0.34 micromol/L for mouse, rat, and human, respectively. However, the corresponding rates of PE metabolism differed dramatically, being 8.3, 2.1, and 0.29 micromol/h/kg in mouse, rat, and human. For a repeated human exposure to 25 ppm PE in air (8 h/day, 5 days/week), PE concentrations in venous blood were simulated. The prediction demonstrates that PE is eliminated so rapidly that it cannot accumulate in the organism. For low exposure concentrations, it became obvious that the rate of uptake into blood by inhalation is limited by the blood flow through the lung and the rate of metabolism is limited by the blood flow through the metabolizing organs.