The following results were obtained recently from our laboratories; in rats with 72-h water deprivation (rats with
dehydration), the hepatic
cytochrome P450 2E1 (
CYP2E1) was three-fold induced with an increase in the
mRNA.
Rehydration of 48-h water-deprived rats for the next 24 h with free access of food (rats with
rehydration) restored
CYP2E1 level to that of control. However,
rehydration of 48-h water-deprived rats for the next 24 h with limited food supply (20% of control) failed to restore the
CYP2E1 level to that of control. Hence, the
CYP2E1 changes in rats with
dehydration and
rehydration resulted from differences in food intakes but not from
dehydration or
rehydration per'se.
Chlorzoxazone (CZX) is metabolized to
6-hydroxychlorzoxazone (
OH-CZX) mainly by
CYP2E1 in rats. Therefore, the pharmacokinetics of CZX and
OH-CZX were compared after
intravenous administration of CZX, 25 mg/kg, to control rats and rats with
dehydration and
rehydration with free access of food. In rats with
dehydration, the amount of 24-h urinary excretion of free
OH-CZX plus its
glucuronide conjugates (Ae (
OH-CZX, 0-24 h,) expressed in terms of intravenous dose of CZX) was significantly greater (45.6 compared with 35.6%) and area under the plasma concentration-time curve from time zero to time infinity (AUC) of CZX was significantly smaller (2190 compared with 3200 micro g min/ml) than those in control rats. The above data indicated that the formation of
OH-CZX increased significantly in rats with
dehydration due to 3-fold induction of
CYP2E1. In rats with
rehydration with free access of food, the Ae (OH-CZX, 0-24 h) (39.0 compared with 35.6%) and AUC of CZX (2870 compared with 3200 micro g min/ml) were restored (comparable) to control levels since the expression of
CYP2E1 in rats with
dehydration returned to control level by
rehydration. The above data indicate that CZX could be used as a chemical probe to assess the activity of
CYP2E1 in rats with
dehydration and
rehydration.