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 variable rates three symmetrical nitrosodialkylamines (N-nitroso-dipropyl, dibutyl and diamyl-amines, NDPA, NDBA, NDAA) into aldehydes and hydroxynitrosamines. Formation of linear aldehydes, convenient probes for alpha-hydroxylation of alkyl chain, and production of hydroxy metabolites of NDPA, NDBA and NDAA were simultaneously monitored by two specific HPLC detection methods. The longer the alkyl chain, the smaller the metabolic rate of the alpha-hydroxylation of the alkyl chain and the greater was the metabolic rate of the corresponding (omega-1)-hydroxy metabolite formation. Thus, the (omega-1)-hydroxylation of the alkyl chain was the major metabolic pathway of NDBA and NDAA in so far as it represented 3.3- and 86-fold of the alpha-hydroxylation. The balance between beta- to omega-hydroxylations and alpha-hydroxylation of carbon atoms of the alkyl chain depends upon its length and also upon the specific P450 isoform(s) involved. The hydroxylation site of the alkyl chain by P450 2E1 depends upon its length. For short alkyl chains, the main pathway was alpha-hydroxylation while for long alkyl chains, such as pentyl, (omega-1)-hydroxylation became the major pathway. The rate of alpha-hydroxylation was shown to be correlated with mutagenesis of 5 dialkylnitrosamines, as inferred from literature data, while the (omega-1)-hydroxylation was inversely correlated. Furthermore, other P450s than P450 2E1, such as P450 3A4 and 2C were shown to be involved in the metabolism of nitrosodialkylamines bearing long alkyl chains.