Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine.

Injection of acetaminophen (APAP) (350 mg/kg body weight) into C57BL/6 mice in which cytochrome P450 (CYP) 1A1/1A2 had been induced produced acute cataract and other ocular tissue damage. Treatment of APAP-injected mice with one of the major organosulfides in garlic oil, diallyl disulfide (DADS) (200 mg/kg body weight), prevented cataract development and prolonged survival time. N-acetyl L-cysteine (NAC) (500 mg/kg body weight), a prodrug that stimulates glutathione synthesis, also prolonged survival time but was effective only weakly to prevent cataract formation. A combination of DADS and NAC completely prevented cataractogenesis, and all of the treated animals survived APAP toxicity. Neither DADS nor NAC inhibited CYP 1A1/1A2 induction as determined by their effect on the induction of hepatic microsomal ethoxyresorufin O-dealkylase (ERD) activity. However, in the in vitro enzyme assay, DADS, but not NAC, was a potent inhibitor of ERD activity (IC50 = 3.5 mM). Treatment with DADS or NAC slowed but did not stop the decrease of hepatic glutathione (GSH) content. At 4 hours after APAP injection, hepatic GSH began to increase only when DADS and NAC were administered together. These results suggest that the protective effect of DADS is due to its inhibition of biotransformation of APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by CYP 1A1/1A2 enzymes and that NAC provides protection by increasing cellular cysteine level and GSH synthesis, thus facilitating detoxification of NAPQI by glutathione conjugation. Assay of plasma glutamate-pyruvate transaminase activity, an indicator of liver necrosis, showed that treatment with DADS and NAC together effectively protected the liver. Therefore, the decrease of GSH as much as 30% of normal concentration, by itself, is not responsible for liver damage. The primary cause of hepatic necrosis is rapid accumulation of NAPQI.