Effect of pentachlorophenol and 2,6-dichloro-4-nitrophenol on the activity of cDNA-expressed human alcohol and aldehyde dehydrogenases.
Pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP), potent inhibitors of phenol sulphotransferases, are frequently used in animal studies to elucidate the role of these enzymes in the biotransformation and toxicity of xenobiotics. An unexpected finding with 1-hydroxymethylpyrene--a strong decrease in the excretion of the corresponding carboxylic acid in rats concurrently treated with PCP-led us to suspect that this sulphotransferase inhibitor may also affect alcohol dehydrogenases (ADHs) and/or aldehyde dehydrogenases (ALDHs). Subsequently we investigated the influence of PCP and DCNP on the activity of cDNA-expressed human ADHs and ALDHs. PCP inhibited all four ADHs studied. The inhibition was strong for ADH3 (K(i) 1.4 microM, K(i)' 5.2 microM, mixed-type) and ADH2 (K(i) 3.7 microM, competitive), but moderate for ADH4 (K(i) 81 microM, competitive) and ADH1C (K(i)' 310 microM, uncompetitive). Activities of ALDH2 and ALDH3A1 were unaffected by PCP (used up to a concentration of 1 mM). In contrast, DCNP primarily inhibited ALDH2 (K(i)=K(i)' 7.4 microM, non-competitive), showed moderate competitive inhibition of ADH2 (K(i) 160 microM) and ADH4 (K(i) 710 microM), but did not affect the remaining enzymes (ADH1C, ADH3 and ALDH3A1). The study demonstrates that caution is required when using putative specific enzyme inhibitors in biotransformation studies.
Kollock
Ronny
R
German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Nutritional Toxicology, 14558 Nuthetal, Germany.
Rost
Katharina
K
Batke
Monika
M
Glatt
Hansruedi
H
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D018076:DNA, Complementary / Q000096:biosynthesis* / Q000235:genetics; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D009596:Nitrophenols / Q000633:toxicity*; D010084:Oxidation-Reduction; D010416:Pentachlorophenol / Q000633:toxicity*; D013056:Spectrophotometry, Ultraviolet
D018076:DNA, Complementary; D006540:Herbicides; D007527:Isoenzymes; D009596:Nitrophenols; C015802:2,6-dichloro-4-nitrophenol; D010416:Pentachlorophenol; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase