The differential effects of hepatotoxicants on the sulfation pathway in rats.
This study characterized the effects of liver damage produced by a variety of hepatotoxicants on several components of the sulfation pathway in rats. Specifically, the concentration of cosubstrate, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), and the hepatic capacity for PAPS synthesis were measured in livers of rats treated with carbon tetrachloride (CCl4), 1,1-dichloroethylene (DCE), alpha-naphthylisothiocyanate (ANIT), aflatoxin B1 (ATX), allyl alcohol (AA), bromobenzene (BB), cadmium chloride (Cd), or thioacetamide (TA). Liver damage was assessed by measuring serum sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALT) activities as well as by histopathological examination. Hepatic PAPS concentration was generally decreased as a result of treatment with hepatotoxicants (35-80% of control), although BB, AA, and ANIT were without effect. Maximal hepatic capacity for PAPS synthesis, determined as the activities of PAPS synthetic enzymes, ATP sulfurylase, and APS kinase, was selectively decreased by the hepatotoxicants. ATP sulfurylase activity was decreased by Cd and TA (55 and 62% of control, respectively), whereas APS kinase activity was decreased by Cd, TA, BB, and DCE (60-77% of control, respectively). In addition, phenol sulfotransferase (PST) activity was measured toward 1- and 2-naphthol in order to determine whether apparent changes in PST activity in damaged livers are substrate-dependent. Treatment with hepatotoxicants generally decreased 1-naphthol-directed PST activity but not PST activity directed toward 2-naphthol. In conclusion, (1) not all xenobiotic-induced liver injury results in decreased hepatic PAPS concentration, (2) some hepatotoxicants decrease PAPS concentration by a mechanism other than decreased cosubstrate synthesis, and (3) the effect of hepatotoxicants on PST activity is dependent upon the choice of substrate used in the enzymatic assay.
Maziasz
T J
TJ
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Liu
J
J
Madhu
C
C
Klaassen
C D
CD
D015058:1-Naphthylisothiocyanate / Q000009:adverse effects; D000433:1-Propanol / Q000009:adverse effects; D016604:Aflatoxin B1 / Q000009:adverse effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015239:Arylsulfotransferase / Q000187:drug effects / Q000378:metabolism; D001969:Bromobenzenes / Q000009:adverse effects; D002104:Cadmium / Q000009:adverse effects; D019256:Cadmium Chloride; D002251:Carbon Tetrachloride / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury; D003600:Cytosol / Q000201:enzymology; D004000:Dichloroethylenes / Q000009:adverse effects; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010724:Phosphoadenosine Phosphosulfate / Q000096:biosynthesis; D020005:Propanols; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism*; D013853:Thioacetamide / Q000009:adverse effects
D001969:Bromobenzenes; D004000:Dichloroethylenes; D020005:Propanols; D013431:Sulfates; D002104:Cadmium; D013853:Thioacetamide; C029297:vinylidene chloride; C006463:allyl alcohol; D010724:Phosphoadenosine Phosphosulfate; D015058:1-Naphthylisothiocyanate; D000433:1-Propanol; D016604:Aflatoxin B1; D002251:Carbon Tetrachloride; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D015239:Arylsulfotransferase; D019256:Cadmium Chloride