IN-VIVO PRODUCTION OF DIFFERENT CHLOROFORM METABOLITES - EFFECT OF PHENOBARBITAL AND BUTHIONINE SULFOXIMINE PRETREATMENT

The regioselective attack on microsomal phospholipid (PL) polar heads (PH) and fatty acyl chains (FC) demonstrated in vitro has been exploit ed for the selective quantitation in vivo of the biochemical damages p roduced by the oxidation and reduction products of CHCl3, metabolism. Five hours after CHCl3 injection (60 mg/kg body weight, ip) to control Sprague-Dawley rats, most of the label covalently bound in the liver was associated to PH, indicating a predominant production of COCl2. Th e levels of radioactivity bound to both PL moieties increased proporti onally when 180 mg/kg body weight (CHCl3)-C-14 was administered. Buthi onine sulf oximine (BSO) pretreatment resulted in a further increase o f binding either to PH or FC. The pretreatment of rats with phenobarbi tal (PB) reduced the PH/FC binding ratio to 3.4, still indicating the predominance of the oxidative metabolism, but giving some indication o f the simultaneous presence of CHCl3 reduction. When reduced glutathio ne (GSH) was depleted by BSO in PB-induced animals prior to (CHCl3)-C- 14 administration, only the level of radioactivity associated with oxi dative intermediates was increased six times. The present results conf irmed that GSH is able to exert an efficient protection mainly toward (CHCl3)-C-14 oxidation intermediates. Furthermore, they indicate that in the liver of the Sprague-Dawley rat the major pathway of CHCl3 biot ransformation is its oxidation and that pretreatment of rats with a GS H-depleting agent (such as BSO) is more relevant than PB induction in enhancing the biochemical damages produced by CHCl3.