Abstract:
:We have reported [Correia et al. (1987) Arch. Biochem. Biophys. 258, 436-443] that administration of 3,5-dicarbethoxy-4-ethyl-2,6-dimethyl-1,4-dihydropyridine (DDEP) to untreated, phenobarbital (PB) pretreated, or dexamethasone (DEX) pretreated rats results in relatively selective inactivation of cytochrome P-450 (P-450) isozymes h (CYP2C11), k (CYP2C6), and p (CYP3A). Such inactivation involves destruction of P-450 prosthetic heme predominantly by N-ethylation in untreated and PB-pretreated rats, whereas in DEX-pretreated rats, it also appears to be associated with prosthetic heme alkylation of the apocytochrome presumably at the active site. The cause for this differential course of DDEP-mediated P-450 heme destruction is unclear. Since this process is absolutely dependent on NADPH-mediated DDEP metabolism and can be reproduced in vitro, in search of mechanistic clues, we have examined DDEP metabolism by liver microsomes from the three rat sources as well as by isolated purified rat liver P-450h and P-450k. HPLC analyses of microsomal incubations of DDEP with NADPH, in the presence of an esterase inhibitor, revealed the presence of two major products: deethylated pyridine (DP) and 4-ethylpyridine (4-EDP) with product ratios (DP/4-EDP) of 1.4, 1.4, and 0.7 for reactions catalyzed by liver microsomes from untreated, PB-pretreated, and DEX-pretreated rats, respectively. The corresponding mean product ratios for P-450h- and P-450k-catalyzed reactions were 4.2 and 5.5, respectively. On the other hand, partition ratios (DP formed/P-450 destroyed) ranged from 12.0, 10.5, and 4.8, respectively, for incubations of liver microsomes from untreated, PB-pretreated, and DEX-pretreated rats to 9.5 and 28.9 for purified P-450h- and P-450k-catalyzed reactions, respectively. However, DP formation in all these microsomal systems was comparable, and although 4-EDP formation was greatly stimulated by DEX pretreatment, it does not appear to be a destructive pathway. In view of this, our findings reported herein suggest that the active site environment of P-450's h, k, and p apparently determines not only the pattern of DDEP metabolism but also the differential course of prosthetic heme destruction.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Sugiyama K,Yao K,Rettie AE,Correia MAdoi
10.1021/tx00012a008subject
Has Abstractpub_date
1989-11-01 00:00:00pages
400-10issue
6eissn
0893-228Xissn
1520-5010journal_volume
2pub_type
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