Detoxification of promutagenic aldehydes derived from methylpyrenes by human aldehyde dehydrogenases ALDH2 and ALDH3A1.
Methylated polycyclic aromatic hydrocarbons can be metabolically activated via benzylic hydroxylation and sulpho conjugation to reactive esters, which can induce mutations and tumours. Yet, further oxidation of the alcohol may compete with this toxification. We previously demonstrated that several human alcohol dehydrogenases (ADH1C, 2, 3 and 4) oxidise various benzylic alcohols (derived from alkylated pyrenes) to their aldehydes with high catalytic efficiency. However, all these ADHs also catalysed the reverse reaction, the reduction of the aldehydes to the alcohols, with comparable or higher efficiency. Thus, final detoxification requires elimination of the aldehydes by further biotransformation. We have expressed two human aldehyde dehydrogenases (ALDH2 and 3A1) in bacteria. All pyrene aldehydes studied (1-, 2- and 4-formylpyrene, 1-formyl-6-methylpyrene and 1-formyl-8-methylpyrene) were high-affinity substrates for ALDH2 (K(m)=0.027-0.9 microM) as well as ALDH3A1 (K(m)=0.78-11 microM). Catalytic efficiencies (k(cat)/K(m)) were higher for ALDH2 than ALDH3A1 by a moderate to a very large margin depending on the substrate. Most important, they were also substantially higher than the catalytic efficiencies of the various ADHs for the reduction the aldehydes to the alcohols. These kinetic properties ensure that ALDHs, and particularly ALDH2, can complete the ADH-mediated detoxification.
Glatt
Hansruedi
H
German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. glatt@dife.de
Rost
Katharina
K
Frank
Heinz
H
Seidel
Albrecht
A
Kollock
Ronny
R
D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000737:chemistry*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000737:chemistry*; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000737:chemistry*; D011721:Pyrenes / Q000737:chemistry*
D000447:Aldehydes; D009153:Mutagens; D011721:Pyrenes; C096127:ALDH2 protein, human; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial