The Dubin-Johnson syndrome (DJS), a hereditary conjugated hyperbilirubinemia, is associated with an impairment of porphyrin metabolism. Total urinary coproporphyrin (CP) excretion and the urinary CP isomer I and III constellation were examined in 15 patients with DJS and 12 unaffected family members, and then compared with 50 unrelated control persons (55 +/- 15 nmol/24 h of total CP: 27 +/- 3% of isomer I; +/- SD). The patients with DJS excreted 80 +/- 7% (+/- SD) of CP isomer I (p less than 0.001). The isomer relation in two young children, 3 and 5 years old, shows an isomer reversal, with isomer I of about 95%. Studies done on four families from our patients with DJS indicate and confirm the autosomal recessive mode of inheritance. Total urinary CP was found to be elevated in subjects with DJS, reaching a mean value of 164 +/- 123 nmol/24 h (upper limit 120 nmol/24 h). Fecal CP isomers I and III were found to be in the usual physiological proportion to each other, but total fecal CP excretion had declined to the lower normal level (10 +/- nmol/g, n = 8). The pathogenetic mechanisms in DJS have not yet been fully worked out. Four possible explanations are currently under discussion: 1. an impaired hepatic excretory function: 2. a uroporphyrinogen III synthase defect; 3. an increase in porphobilinogen deaminase (uroporphyrinogen synthase) activity, or 4. a membrane-associated transport disorder with secondary metabolic changes of the isomer pool and enzyme activities.