Effect of the suicide substrate 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine on the metabolism of xenobiotics and on cytochrome P-450 apoproteins.
Treatment of rats with the cytochrome P-450 suicide substrate, 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP), produced a 95% inhibition of the in vivo demethylation of either aminopyrine or morphine within 2 hr. One-carbon metabolism of formaldehyde or formate to carbon dioxide was not altered. DDEP also produced a time-dependent decrease in total hepatic microsomal cytochrome P-450 but had no effect on either NADPH-cytochrome c reductase or p-nitrophenol glucuronyl-transferase activities up to 24 hr after administration. A rapid decrease in rat liver microsomal aniline hydroxylation and ethoxyresorufin deethylation was observed in vitro following DDEP administration. Although in vitro testosterone metabolism to 16 alpha-, 16 beta-, and 2 alpha-hydroxy metabolites was depressed profoundly by DDEP in microsomes from untreated and 3-methylcholanthrene-treated animals, 7 alpha-hydroxylation of testosterone was much less affected. Immunochemical quantification of various microsomal cytochrome P-450 protein moieties showed that cytochromes P-450 beta NF-B, P-450UT-A, P-450PCN-E, and P-450PB-C were decreased in hepatic microsomes from DDEP-treated rats. However, the protein moiety of cytochrome P-450UT-H was not diminished and the immunoreactive protein for cytochromes P-450UT-F, P-450PB-B, and P-450ISF-G was only slightly decreased. These results show that DDEP treatment leads to marked decreases in holoprotein and apoproteins of many but not all hepatic microsomal cytochrome P-450 isozymes.
Tephly
T R
TR
Black
K A
KA
Green
M D
MD
Coffman
B L
BL
Dannan
G A
GA
Guengerich
F P
FP
D000818:Animals; D001059:Apoproteins / Q000032:analysis*; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000276:immunology; D003640:Dealkylation; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000378:metabolism
D001059:Apoproteins; D002250:Carbon Radioisotopes; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D011725:Pyridines; D013256:Steroids; C030826:3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine; D002245:Carbon Dioxide; D003997:Dicarbethoxydihydrocollidine; D003577:Cytochrome P-450 Enzyme System