Zoxazolamine-induced paralysis in two rat substrains: differences in hepatic drug metabolism

Aldehyde dehydrogenase (ALDH) is involved in the metabolism of endogenous a nd exogenous aldehydes originating from biogenic amines, lipids, food and d rugs. Rat liver contains at least two cytosolic ALDHs that can be stimulate d by inducers of drug metabolism. Phenobarbital- type inducers increase ALD H1 activity while polycyclic aromatic hydrocarbons (such as benzo[a]pyrene) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increase ALDH3c isoenzyme a ctivity. Two rat substrains were isolated according to a different inductio n of hepatic ALDH after treatment with phenobarbital (PB). Animals that res ponded to treatment (RR) and those that did not respond (rr) were inbred an d divided into two homogenous groups. These animals constituted an ideal ex perimental model due to their common origin. Apart from the dramatic induct ion of cytosolic ALDH1 and ALDH3c, the effects of PB on pentoxy-, ethoxy an d methoxy-resorufin-O-dealkylase (P-, E-, and MROD) between the two substra ins were also studied. 3-Methylcholanthrene (3MC) greatly increased ALDH3c levels in both substrains, although it was slightly more pronounced in the rr rats, in which it was assessed either as ALDH3c or as total cytosolic AL DH. A similar trend was also noted in EROD, PROD and MROD activities. Dealk ylation of the methoxy group was found to be statistically different betwee n the two substrains (rr > RR). The relevance of the biochemical findings w ith the in vivo hepatic capacity for drug metabolism was investigated by me asuring the duration of zoxazolamine paralysis. Both animal substrains were tested with zoxazolamine either without pretreatment or after administrati on of PB or 3MC: the paralysis produced by zoxazolamine lasted for a longer period in rr than in RR rats. After pretreatment with PB, the duration of paralysis was greatly reduced, but the differences between the two substrai ns remained. Pretreatment with various doses of 3MC produced differences.