Abstract:
:We investigated the role played by monoclonal antibody defined classes of cytochrome P-450 in the metabolism of antipyrine, aminopyrine and theophylline. Two enzyme inhibitory monoclonal antibodies (MAb 1-7-1 and MAb 2-66-3) raised to two forms of cytochrome P-450 were used. Microsomes were prepared from the livers of untreated, 3-methylcholanthrene (MC)-treated, and phenobarbital (PB)-treated male Wistar rats. Addition of either monoclonal antibody to hepatic microsomes from untreated rats had a negligible effect on the metabolism of aminopyrine, antipyrine or theophylline. These results indicate that the constitutive enzymes responsible for metabolism of these three drugs differ from the MAb inhibitable enzymes responsible for transformation of these drugs in induced microsomes. In microsomes from MC- and PB-treated rats, however, the two MAbs differentially inhibited individual pathways. For example, at 20 mM aminopyrine, as much as 55% of 4-amino-antipyrine (4-AA) formation arose from the family of cytochrome P-450 isozymes that were not inhibited for 4-AA formation at 4 mM aminopyrine and 4-methylaminoantipyrine (4-MAA) formation at either concentration. Thus, the enzyme that functions at 20 mM aminopyrine in 4-MAA formation differs from that which functions at 4 mM aminopyrine in the formation of 4-AA or 4-MAA. Addition of MAbs to induced microsomes revealed at least four isozymes with overlapping specificities involved in antipyrine and theophylline metabolism. Each MAb-inhibitable pathway and the isozymes associated with it were classified into one of three epitope families: those pathways inhibited by both MAbs, those inhibited only by the MAb raised against PB-inducible P-450 isozymes, and those inhibited only by the MAb raised against 3-MC-inducible P-450 isozymes. A fourth group of pathways consisted of those unaffected by addition of either monoclonal antibody. Analysis of metabolism with these two MAbs suggests more extensive heterogeneity of the isozymes that biotransform these drugs than previously recognized.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Slusher LB,Park SS,Gelboin HV,Vesell ESdoi
10.1016/0006-2952(87)90604-6subject
Has Abstractpub_date
1987-07-15 00:00:00pages
2359-67issue
14eissn
0006-2952issn
1873-2968pii
0006-2952(87)90604-6journal_volume
36pub_type
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