The influence of aging on dimethylnitrosamine-demethylase enzyme kinetics in rat liver microsomes.
To investigate the observed age-related increased susceptibility to chemically-induced carcinogenesis, liver microsomes from 12- or 36-month-old rats either untreated or maximally induced with phenobarbital or isoniazid were used to determine the Vmax and Km for dimethylnitrosamine-demethylase (DMNA-d). A decrease in cytochrome P450 content between young and old animals was observed in the untreated group, but no change was seen in the treated animals. Inducer-related increases were observed after phenobarbital treatment and in the 36-month-old isoniazid-treated group. The Vmax for DMNA-d did not change between 12 and 36 months of age in all experimental groups, but significant changes between the young and old age-group and inducer-related differences were observed in the Km,app for DMNA-d. A high correlation was found between the Cl(int) (= Vmax/Km,app) of DMNA-d and the Vmax of p-nitrophenol-hydroxylation, indicating a major role for CYP2E1 in the metabolism of DMNA-d. The observed changes in the cytochrome-P450 levels and the reduced affinity in DMNA-d metabolism in the untreated group in this study is another indication that aging predominately affects the activity of some constitutive cytochrome P450 enzymes but not the activity of the inducible types of P450.
TNO Prevention and Health, Leiden, The Netherlands.
J G
JG
Van Asten
J M
JM
Te Koppele
G J
GJ
Horbach
D000375:Aging / Q000378:metabolism*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000633:toxicity*; D051381:Rats; D011914:Rats, Inbred BN
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D007538:Isoniazid; D010634:Phenobarbital