Hepatic glutathione depletion and impaired bromosulphthalein clearance early after paracetamol overdose in man and the rat.

1. Plasma clearance of bromosulphthalein was impaired in patients within 8 h, and in rats within 2 h , of paracetamol overdose, before biochemical signs of liver damage had appeared. 2. Paracetamol and bromosulphthalein competed for uptake into the liver and excretion into the bile. Impaired hepatic uptake of bromosulphthalein could also be demonstrated in man at doses of the drug within the therapeutic range. 3. In patients studied a smaller proportion of bromosulphthalein was retained in the plasma as the glutathione conjugate after an overdose than after therapeutic doses. This effect could be reproduced in the rat and shown to be due to depletion of hepatic glutathione and to impairment in the activity of the enzyme glutathione-S-aryl transferase. 4. These studies provide further evidence that depletion of hepatic glutathione occurs after paracetamol overdose in man, as in the experimental animal, allowing the subsequent accumulation and binding of a toxic metabolite of the drug within liver cells. Impaired enzymic conjugation of the toxic metabolite with hepatic reduced glutathione may also be important in this situation.