Search

Eleven patients with porphyria cutanea tarda were studied. Biochemical confirmation of the clinical diagnosis required only determination of the total urine porphyrin concentration in a sample of urine voided on rising in the morning. The patients were divided for convenience of discussion into four groups differing in age, sex and etiologic factors. Of the six patients in whom a liver biopsy was done one was shown to have micronodular cirrhosis. Except for a modest elevation in the serum glutamic oxaloacetic transaminase values when the patients were first seen, no evidence was found for liver disease apart from the presence of porphyria cutanea tarda. One patient recovered solely by abstaining from alcohol consumption. Five patients underwent phlebotomy; their iron stores had been found to be between 2 and 3 g. Decreasing urine porphyrin values correlated well with decreasing serum ferritin values during the course of phlebotomy. Porphyria cutanea tarda, which is due to a deficiency of uroporphyrinogen decarboxylase, is manifested in association with alcohol abuse, estrogen therapy, exposure to chlorinated hydrocarbons or increased tissue iron stores, or a combination of these factors. Although relatively uncommon, this condition raises important and unresolved issues regarding the hepatotoxicity of alcohol, estrogens, chlorinated hydrocarbons and iron.

SVA was used to separate liver cells from rats pretreated for 3 days with PB (40 mg/kg intraperitoneally, twice daily) or 3-MC (50 MG/KG AS A SINGLE INJECTIOn). Twelve fractions of cells were collected with s's ranging from 97 mm/hr (fraction1) to 25 mm/hr (fraction 12). Cells in each fraction were sized and counted electronically. PB caused the average volume of the largest cells recovered (fraction 1) to increase to 16, 725 micrometer3 from 10,500 micrometer3 previously reported in untreated animals. The number of cells recovered in the fast-sedimenting fractions (1 to 6) also increased, but there was only a small rise in the average model volume of hepatocytes determined prior to SVA. In cell suspensions analyzed after PB treatment no evidence was found for a discontinuity in the distribution of density-volume characteristics as previously described in hepatocytes from untreated rats. As expected, prior to sedimentation analysis, hepatocyte suspensions from rats treated with PB contained increased cytochrome P-450. The average ratio (n = 4) of P-450 in separated to unseparated cells ranged from 2.75 (fractions 1 + 2) to 0.38 (fractions 11 + 12), giving a 6.8-fold range in quantity of cytochrome per cell. Over this range, cell volume increased 4.2-fold, indicating a gradient in P-450 concentration similar to that previously reported to exist in cells from untreated rat liver. The gradient for AHH activity was 6.7-fold, suggesting that activity of MFO's paralleled the increase in cytochrome concentration. 3-MC pretreatment caused no significant increase in either size or number of cells in the fast-sedimenting fractions, but the discontinuity in density-volume characteristics which distinguished fast and slow sedimenting cells of untreated rats became marked. Furthermore, both the size and number of cells recovered in fractions 7 to 11 (which include the modal peal volume of unseparated hepatocytes) were increased. The gradient of P-450 (OR P1-450) was less steep in 3-MC-treated cells with pooled fractions 1 and 2 containing an average of 4.62 times as much cytochrome as fractions 11 and 12. The gradient for AHH was 4.29 times. The range of cell volume was 3.3-fold over this range. Additional experimental work was performed to determine whether P-450, AHH, or NADPH cytochrome c reductase exhibited differences in activity or concentration per unit of cell volume between cells on either side of fraction 7 where discontinuity had been noted. Each variable was expressed per unit of cell volume in fractions 5 and 9; ratios were compared but were indistinguishable from unity. It was concluded that induction of MFO activity had occurred equally in both populations of cells. Densities were calculated from s and cell volume. Noticeable loss of density followed PB treatment in cells of all sizes. 3-MC had less of an effect on density but enhanced the increment in density observed at fraction 7, which corresponds to the division between cells with distinct sedimentation characteristics...

The metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol) by prostaglandin synthetase and cytochrome P-450-dependent monooxygenases was studied using enriched fractions of Clara cells and alveolar type II cells from rat lung. Arachidonic acid-fortified fractions enriched in Clara cells and alveolar type II cells metabolized BP-7,8-diol to the 7,10/8,9-tetrol of benzo(a)pyrene and the 7/8,9,10-tetrol of benzo(a)pyrene. These tetrols are formed upon solvolysis of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha- epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene (BP diol-epoxide I). Arachidonic acid-dependent metabolism of BP-7,8-diol to BP diol-epoxide I in enriched Clara cells and alveolar type II cells was completely inhibited by indomethacin, a classical inhibitor of prostaglandin synthetase. Enriched Clara cells and alveolar type II cells also metabolized BP-7,8-diol to BP diol-epoxide I in the presence of NADPH. Amounts of BP diol-epoxide I-derived tetrols formed from BP-7,8-diol by the prostaglandin synthetase-dependent and the cytochrome P-450-dependent pathways varied significantly between the two pulmonary cell fractions examined. In fractions enriched in Clara cells, cytochrome P-450-dependent BP-7,8-diol oxidation was higher than was prostaglandin synthetase-dependent BP-7,8-diol oxidation; while in fractions of alveolar type II cells, prostaglandin synthetase-dependent BP-7,8-diol oxidation to BP diol-epoxide I predominated. Pretreatment of rats with beta-naphthoflavone resulted in a 2- to 3-fold increase in BP diol-epoxide I formation by prostaglandin synthetase and cytochrome P-450-dependent monooxygenases in both enriched Clara cells and alveolar type II cells. These increases in BP-7,8-diol oxidation to BP diol-epoxide I appear to be due to induction of the two enzymatic pathways in both pulmonary cell types. No qualitative changes in the pattern of BP-7,8-diol metabolism by either enzymatic pathway in enriched Clara cells or alveolar type II cells were observed following beta-naphthoflavone treatment. The results suggest that pulmonary prostaglandin synthetase may serve as either an additional or an alternative bioactivating enzyme to the cytochrome P-450-dependent monooxygenases for the formation of reactive chemical carcinogens in the lung.