G. Bellec et al., CYTOCHROME-P450 METABOLIC DEALKYLATION OF 9 N-NITROSODIALKYLAMINES BYHUMAN LIVER-MICROSOMES, Carcinogenesis, 17(9), 1996, pp. 2029-2034
The metabolic dealkylation of nine nitrosodialkylamines, including fiv
e symmetrical (nitrosodimethylamine, nitrosodiethylamine, nitrosodipro
pylamine, nitrosodibutylamine and nitrosodiamylamine) and four asymmet
rical nitrosodialkylamines (nitrosomethylethylamine, nitrosomethylprop
ylamine, nitrosomethylbutylamine and nitrosomethylamylamine), was inve
stigated in 14 samples of human liver microsomes, All these nitrosodia
lkylamines were dealkylated to aldehydes that were separated by revers
ed phase HPLC and UV detected as dinitrophenylhydrazones. As the lengt
h of the alkyl chain increased from methyl to pentyl, dealkylation of
symmetrical nitrosodialkylamines became less efficiently catalyzed by
cytochrome P450, Conversely, oxidation of the methyl moiety of asymmet
rical nitrosomethylalkylamines increased with the size of the alkyl mo
iety, while dealkylation of the longer alkyl group decreased, N-Dealky
lase activities were significantly correlated with P450 activities mea
sured in human liver microsomes, These catalytic activities involve CY
P2A6 (coumarin 7-hydroxylation), CYP2C (mephenytoin 4-hydroxylation an
d tolbutamide hydroxylation), CYP2D6 (dextromethorphan O-demethylation
), CYP2E1 (chlorzoxazone and p-nitrophenol hydroxylation) and CYP3A4 (
nifedipine oxidation), By using 10 heterologously expressed P450s, it
was shown that nitrosodimethylamine was mainly demethylated by CYP2E1.
However, such enzyme specificity was lost with increasing size of the
alkyl group, Therefore, the chain length of the alkyl group of nitros
odialkylamines determined the P450 involved in its oxidation. All thes
e results emphasize that the catalytic site of P450 2E1 has a geometri
c configuration such that only small molecules like nitrosodimethylami
ne fit favorably within the putative active site of the enzyme, Furthe
rmore, there is good evidence that P450s other than P450 2E1, such as
P450 2A6, 2C8/2C9/2C19 and 3A4, are involved in the metabolism of nitr
osodialkylamines bearing bulky alkyl chains.