The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low doses of acetaminophen converted to the mercapturic acid metabolite was highest in the most susceptible species (hamsters, mice), and lowest in the more resistant species (rat). Pretreatment regimens known to potentiate the hepatotoxicity increased mercapturic acid formation whereas treatments which protect from liver damage decreased mercapturic acid formation. The data suggest that the activity of the mercapturic acid-forming pathway in vivo reflects the activity of the hepatotoxic pathway. As the dose of acetaminophen was increased to hepatotoxic levels, the fraction of the dose excreted as the mercapturic acid decreased markedly, commensurate with the known depletion of hepatic glutathione under these conditions. It is suggested that the normal metabolic intermediate which conjugates with glutathione in the mercapturic acid pathway is also the electrophilic metabolite which in the absence of glutathione arylates hepatic macromolecules and causes cell death.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of polypeptides that includes NGF, NT-3, NT-4/5 and NT-6. Although neurotrophins are known to be expressed in teleost fishes little is known about their functions in the development of these vertebrates. We are therefore studying BDNF in the zebrafish, Danio rerio. The structure of zebrafish BDNF mRNA was established using PCR and cDNA cloning. The encoded BDNF was 91% identical to mammalian BDNF. Southern blot analysis revealed a unique BDNF gene. Northern blot analysis detected two heterogeneous populations of BDNF transcripts centered at 1.6 and 2 kb. BDNF transcripts were first measurable 24 h post-fertilization (pf). Their abundance relative to total transcripts increased 6-fold between 1 day and 3 days pf and again 2-fold by 7 days pf. In situ hybridization analyses of 4-day-old larvae revealed BDNF transcripts in the retina, brain, otic vesicle, pectoral fin and the hair cells of the neuromast. The early onset and cellular sites of expression suggest that BDNF functions in nervous system and fin development in the zebrafish.