Dockham P A, Sreerama L, Sladek N E
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
Drug Metab Dispos. 1997 Dec;25(12):1436-41.
Detoxification of cyclophosphamide is effected, in part, by hepatic class 1 aldehyde dehydrogenase (ALDH-1)-catalyzed oxidation of aldophosphamide, a pivotal aldehyde intermediate, to the nontoxic metabolite, carboxyphosphamide. This enzyme is found in erythrocytes as well. Detoxification of aldophosphamide may also be effected by enzymes, viz. certain aldo-keto reductases, that catalyze the reduction of aldophosphamide to alcophosphamide. Such enzymes are also found in erythrocytes. Not known at the onset of this investigation was whether the contribution of erythrocyte ALDH-1 and/or aldo-keto reductases to the overall systemic detoxification of circulating aldophosphamide is significant. Thus, NAD-linked oxidation and NADPH-linked reduction of aldophosphamide catalyzed by relevant erythrocyte enzymes were quantified. ALDH-1-catalyzed oxidation of aldophosphamide (160 microM) to carboxyphosphamide occurred at a mean (+/- SD) rate of 5.0 +/- 1.4 atmol/min/rbc (red blood cell). Aldo-keto reductase-catalyzed reduction of aldophosphamide (160 microM) to alcophosphamide occurred at a much slower rate, viz. 0.3 +/- 0.2 atmol/min/rbc. Thus, at a pharmacologically relevant concentration of aldophosphamide, viz. 1 microM, estimated aggregate erythrocyte ALDH-1-catalyzed aldophosphamide oxidation, viz. 2.0 micromol/min, was only about 3% of estimated aggregate hepatic enzyme-catalyzed aldophosphamide oxidation, viz. 72 micromol/min; however, this rate is greater than the estimated flow-limited rate of aldophosphamide delivery to the liver by the blood, viz. 1.5 micromol/min. These observations/considerations suggest an important in vivo role for erythrocyte ALDH-1 in systemic aldophosphamide detoxification. Erythrocyte ALDH-1-effected oxidation of other aldehydes to their corresponding acids, e.g. retinaldehyde to retinoic acid, may also be of pharmacological and/or physiological significance since a wide variety of aldehydes are known to be substrates for ALDH-1.
环磷酰胺的解毒作用部分是通过肝脏1类醛脱氢酶（ALDH - 1）催化关键醛中间体醛磷酰胺氧化为无毒代谢物羧基磷酰胺来实现的。这种酶在红细胞中也有发现。醛磷酰胺的解毒作用也可能由某些酶，即特定的醛酮还原酶催化醛磷酰胺还原为醇磷酰胺来实现。这类酶同样存在于红细胞中。在本研究开始时尚不清楚红细胞ALDH - 1和/或醛酮还原酶对循环醛磷酰胺整体全身解毒作用的贡献是否显著。因此，对相关红细胞酶催化的醛磷酰胺的NAD连接氧化和NADPH连接还原进行了定量。ALDH - 1催化醛磷酰胺（160微摩尔）氧化为羧基磷酰胺的平均（±标准差）速率为5.0±1.4阿托摩尔/分钟/红细胞（红细胞）。醛酮还原酶催化醛磷酰胺（160微摩尔）还原为醇磷酰胺的速率要慢得多，即0.3±0.2阿托摩尔/分钟/红细胞。因此，在药理学相关浓度的醛磷酰胺，即1微摩尔时，估计红细胞ALDH - 1催化的醛磷酰胺氧化总量，即2.0微摩尔/分钟，仅约为估计肝脏酶催化的醛磷酰胺氧化总量，即72微摩尔/分钟的3%；然而，该速率大于估计的血液将醛磷酰胺输送到肝脏的流量限制速率，即1.5微摩尔/分钟。这些观察结果/考虑因素表明红细胞ALDH - 1在全身醛磷酰胺解毒中具有重要的体内作用。红细胞ALDH - 1将其他醛氧化为相应酸的作用，例如将视黄醛氧化为视黄酸，也可能具有药理学和/或生理学意义，因为已知多种醛是ALDH - 1的底物。
