Shifting necrosis: butylated hydroxytoluene (BHT) and phenobarbital move cocaine-induced hepatic necrosis across the lobule.

Cocaine (60 mg/kg i.p.) caused centrilobular necrosis in the livers of 55% of DBA/2Ha mice. Pretreatment with phenobarbital (PB, 3 x 80 mg/kg i.p.) increased the incidence of necrosis to 70% and shifted this damage to the midzonal region. Pretreatment with butylated hydroxytoluene (BHT, 0.1% in diet) increased the severity of the centrilobular damage and increased the incidence to 90%. Combined treatment with both PB and BHT shifted the site of necrosis to the periportal region of the liver, and induced necrosis in all animals. Microsomal malondialdehyde (MDA) did not reflect the extent of the damage and/or correlate with the site of damage. These results argue against a causal role for lipid peroxidation in the mechanism of cocaine hepatotoxicity, and demonstrate that prior exposure to enzyme-inducing agents can increase sensitivity and dramatically alter the site of cell damage.