Inhibition of human aldehyde dehydrogenase 1 by the 4-hydroxycyclophosphamide degradation product acrolein.
In a previous study, we observed that the elimination clearance of 4-hydroxycyclophosphamide (HCY) in patients receiving cyclophosphamide (CY) 60 mg/kg/day by 1-h i.v. infusion for 2 consecutive days decreased from day 1 to day 2 due to an apparent decrease in human aldehyde dehydrogenase 1 (ALDH1) activity. Here, the mechanism for the decrease in ALDH1 activity after CY administration was investigated. In human liver cytosol incubations, HCY inhibited ALDH activity mainly through its degradation product acrolein, whereas carboxyethylphosphoramide mustard inhibited ALDH activity only at supraclinical concentrations. Other CY metabolites evaluated, phosphoramide mustard and chloroacetaldehyde, did not inhibit ALDH. The inhibition of ALDH1 activity by acrolein in incubations with human erythrocyte ALDH1 was competitive with a Ki of 0.646 microM. The inhibition was independent of preincubation time and reversible by dialysis. The percentage of inhibition of ALDH1 activity in vivo by acrolein in patients receiving CY was calculated based on the in vitro Ki of acrolein, the in vitro Km of HCY, and the in vivo peak blood concentrations of HCY and acrolein. The calculations indicated that the activity of ALDH1 was inhibited by 85, 88, and 91% on days 1, 2, and 3 (24 h after the dose on day 2) of CY administration, respectively. The increase in ALDH1 inhibition with time is consistent with the decrease in HCY elimination clearance and the increase in HCY area under the plasma concentration time curve with time.
Ren
S
S
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Kalhorn
T F
TF
Slattery
J T
JT
D000171:Acrolein / Q000378:metabolism / Q000494:pharmacology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000080924:Aldehyde Dehydrogenase 1 Family; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D050697:Retinal Dehydrogenase
D004791:Enzyme Inhibitors; D007527:Isoenzymes; C012358:4-hydroxycyclophosphamide; D000171:Acrolein; D003520:Cyclophosphamide; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase