Metabolism of NAD(P)H by blood components. Relevance to bioreductively activated prodrugs in a targeted enzyme therapy system

Biochem Pharmacol. 1992 Aug 18;44(4):631-5. doi: 10.1016/0006-2952(92)90396-z.


NADH was metabolized both by serum components and at the cell surface. The metabolism by serum was either oxidation to NAD+, or hydrolysis of the pyrophosphate to yield nicotinamide mononucleotide (reduced) (NMNH) and AMP. NMNH was further hydrolysed to yield nicotinamide riboside (reduced) (NRH), which was stable. NAD+ was hydrolysed (although at a slower rate than was NADH), but was also reduced to yield NADH. The reduction of NAD+ was catalysed by the enzyme serum L(+)lactate dehydrogenase (EC and was dependent on the concentration of L(+)lactate in the serum. NADPH was hydrolysed in a similar manner to NADH but not oxidized by serum. NADH generated from NAD+ by serum derived from human, foetal calf and horse sources was capable of driving the bioreductive activation of CB 1954 by the enzyme DT diaphorase. Cell surfaces oxidized NADH to NAD+, but did not oxidize NADPH or NRH. These observations suggest that NAD(P)H would be unsuitable as a source of reducing equivalents for the bioreductive activation of prodrugs by a reductase enzyme in Antibody Directed Enzyme Prodrug Therapy (ADEPT). In contrast, NAD+ (which could act as a source of NADH) and NRH could avoid the shortcomings of NAD(P)H, and act as suitable cofactors for an enzyme in an ADEPT system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Aziridines / metabolism
  • Biotransformation
  • Blood
  • Blood Coagulation
  • Cattle
  • Dihydrolipoamide Dehydrogenase / metabolism
  • Horses
  • Humans
  • Hydrolysis
  • Lactates / blood
  • NAD / metabolism*
  • NADP / metabolism*
  • Niacinamide / metabolism
  • Oxidation-Reduction
  • Prodrugs / metabolism*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Aziridines
  • Lactates
  • Prodrugs
  • NAD
  • Niacinamide
  • NADP
  • tretazicar
  • Dihydrolipoamide Dehydrogenase