Lidocaine metabolism by human cytochrome P-450s purified from hepatic microsomes: comparison of those with rat hepatic cytochrome P-450s.
The metabolism of lidocaine by human hepatic microsomes and purified human cytochrome P-450s, P-450NF (P450IIIA4), P-450MP (a P450IIC form) and P-450PA (P450IA2) was examined and their metabolism was compared with that by rat hepatic cytochrome P-450s. Human hepatic microsomes produced monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-LID) from lidocaine. In a reconstituted system with dilauroylphosphatidylcholine, P-450NF efficiently produced MEGX. P-450PA was not efficient in lidocaine N-deethylation (formation of MEGX) but produced 3-OH-LID. P-450NF and P-450MP did not produce 3-OH-LID. Lidocaine N-deethylation activity of P-450NF was enhanced in a modified reconstituted system with a phospholipid mixture and sodium cholate. P-450NF appears to be an ortholog to rat P450 PB-1 (P450IIIA2). Anti-P450 PB-1 antibody cross-reacted with P-450NF and efficiently inhibited lidocaine N-deethylation in human hepatic microsomes. The correlation of lidocaine N-deethylation activity with the concentration of P-450NF determined immunochemically with anti-P450 PB-1 antibody was good (r = 0.81). In addition, correlation between P-450NF content estimated with anti-P450 PB-1 and anti-P-450NF preparations was good (r = 0.96). These results suggest that rat P450 PB-1 and human P-450NF have closely related properties and P-450NF is the major enzyme involved in lidocaine N-deethylation in human hepatic microsomes.
Imaoka
S
S
Laboratory of Chemistry, Osaka City University Medical School, Japan.
Enomoto
K
K
Oda
Y
Y
Asada
A
A
Fujimori
M
M
Shimada
T
T
Fujita
S
S
Guengerich
F P
FP
Funae
Y
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000478:Alkylation / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008012:Lidocaine / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000906:Antibodies; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine