CYTOCHROME-P450 HYDROXYLATION OF CARBON-ATOMS OF THE ALKYL CHAIN OF SYMMETRICAL N-NITROSODIALKYLAMINES BY HUMAN LIVER-MICROSOMES

A panel of 14 human liver microsomal preparations metabolized at varia ble rates three symmetrical nitrosodialkylamines (N-nitroso-dipropyl, dibutyl and diamyl-amines, NDPA, NDBA, NDAA) into aldehydes and hydrox ynitrosamines. Formation of linear aldehydes, convenient probes for al pha-hydroxylation of alkyl chain, and production of hydroxy metabolite s of NDPA, NDBA and NDAA were simultaneously monitored by two specific HPLC detection methods. The longer the alkyl chain, the smaller the m etabolic rate of the alpha-hydroxylation of the alkyl chain and the gr eater was the metabolic rate of the corresponding (omega-1)-hydroxy me tabolite formation. Thus, the (omega-1)-hydroxylation of the alkyl cha in was the major metabolic pathway of NDBA and NDAA in so far as it re presented 3.3- and 86-fold of the alpha-hydroxylation. The balance bet ween beta- to omega-hydroxylations and alpha-hydroxylation of carbon a toms of the alkyl chain depends upon its length and also upon the spec ific P450 isoform(s) involved. The hydroxylation site of the alkyl cha in by P450 2E1 depends upon its length. For short alkyl chains, the ma in pathway was alpha-hydroxylation while for long alkyl chains, such a s pentyl, (omega-1)-hydroxylation became the major pathway. The rate o f alpha-hydroxylation was shown to be correlated with mutagenesis of 5 dialkylnitrosamines, as inferred from literature data, while the (ome ga-1)-hydroxylation was inversely correlated. Furthermore, other P450s than P450 2E1, such as P450 3A4 and 2C were shown to be involved in t he metabolism of nitrosodialkylamines bearing long alkyl chains.