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CYP3A12  -  cytochrome P-450 3A12

Canis lupus familiaris

 
 
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Disease relevance of CYP3A12

 

High impact information on CYP3A12

  • Their selectivity was evaluated using phenacetin O-deethylation (CYP1A), diazepam (DZ) N1-demethylation (CYP2B11), diclofenac 4'-hydrxylation (CYP2C21), bufuralol 1'-hydroxylation (CYP2D11), and DZ C3-hydroxylation (CYP3A12) activities in dog liver microsomes (DLM) [2].
  • Therefore, it is concluded that one can attempt to conduct P450 reaction phenotype studies with DLM using MBA and KET as selective inhibitors of CYP2B11 and CYP3A12, respectively [2].
  • In fact, complete inhibition of CYP3A12-dependent DZ C3-hydroxylation was possible at a low KET concentration (1 microM) [2].
  • The sequence encodes a protein of 503 amino acids with 33 nucleotide differences conferring 22 amino acid substitutions when compared with the previously identified canine CYP3A12 enzyme [3].
  • CYP2B11 and CYP3A12 effectively catalyzed the N1-demethylation and C3-hydroxylation of diazepam (and its derivatives), whereas CYP3A12 and CYP2D15 catalyzed exclusively the N- and O-demethylation, respectively, of dextromethorphan [4].
 

Biological context of CYP3A12

 

Anatomical context of CYP3A12

  • Differences in mRNA levels of PPARalpha and MRP2 in colon and MDR1, MRP2, CYP3A12 and SULT1A1 in duodenum may be indicative for enteropathy in FRD and (or) IBD dogs relative to healthy dogs [7].
  • In jejunal microsomes, CYP3A12 activity doubled with bergamottin treatment [8].
  • To study the effect of bergamottin on P450 enzymes, beagle dog liver and jejunum was harvested after a 10-day dosing regimen of bergamottin (1 mg/kg) p.o. per day; microsomes were prepared and analyzed for CYP3A12, CYP2B11, CYP1A1/2, and tolbutamide hydroxylase activity [8].
 

Associations of CYP3A12 with chemical compounds

  • CYP3A12 was shown to primarily oxidize testosterone at 16alpha-, 2alpha/2beta-, and 6beta-positions [4].
  • In contrast to MBA, KET was identified as a potent and selective reversible (competitive) inhibitor of CYP3A12 (K(I) = 0.13-0.33 microM) [2].
  • The greatest increase in CYP2B11 markers produced by tebufelone treatment ranged from 2- to 3-fold, whereas the increase in CYP3A12 markers ranged from 5- to 10-fold [9].
  • The changes in hepatic ultrastructure and increases in CYP2B11 and CYP3A12 markers produced by tebufelone in dogs are similar to that reported for phenobarbital [9].
  • Tebufelone treatment increased NADPH-dependent cytochrome c reductase, total P450, and indicators of CYP2B11 (chloramphenicol covalent binding and immunochemically determined 2B11) and CYP3A12 (erythromycin N-demethylase, triacetyloleandomycin spectral complex formation, testosterone 6 beta-hydroxylase, and immunochemically determined 3A12) [9].
 

Other interactions of CYP3A12

  • Therefore, the 6beta- and 16alpha-hydroxylation of testosterone can potentially be employed as markers of CYP3A12 and CYP2C21 (at low concentration), respectively [4].
 

Analytical, diagnostic and therapeutic context of CYP3A12

References

  1. Escherichia coli expression and substrate specificities of canine cytochrome P450 3A12 and rabbit cytochrome P450 3A6. Born, S.L., Fraser, D.J., Harlow, G.R., Halpert, J.R. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  2. Selective inhibition of dog hepatic CYP2B11 and CYP3A12. Lu, P., Singh, S.B., Carr, B.A., Fang, Y., Xiang, C.D., Rushmore, T.H., Rodrigues, A.D., Shou, M. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  3. Isolation, heterologous expression and functional characterization of a novel cytochrome P450 3A enzyme from a canine liver cDNA library. Fraser, D.J., Feyereisen, R., Harlow, G.R., Halpert, J.R. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  4. Substrate specificity and kinetic properties of seven heterologously expressed dog cytochromes p450. Shou, M., Norcross, R., Sandig, G., Lu, P., Li, Y., Lin, Y., Mei, Q., Rodrigues, A.D., Rushmore, T.H. Drug Metab. Dispos. (2003) [Pubmed]
  5. In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes. Kuroha, M., Kuze, Y., Shimoda, M., Kokue, E. Am. J. Vet. Res. (2002) [Pubmed]
  6. mRNA and protein expression of dog liver cytochromes P450 in relation to the metabolism of human CYP2C substrates. Graham, M.J., Bell, A.R., Crewe, H.K., Moorcraft, C.L., Walker, L., Whittaker, E.F., Lennard, M.S. Xenobiotica (2003) [Pubmed]
  7. Nuclear receptor and target gene mRNA abundance in duodenum and colon of dogs with chronic enteropathies. Greger, D.L., Gropp, F., Morel, C., Sauter, S., Blum, J.W. Domest. Anim. Endocrinol. (2006) [Pubmed]
  8. The effect of bergamottin on diazepam plasma levels and P450 enzymes in beagle dogs. Sahi, J., Reyner, E.L., Bauman, J.N., Gueneva-Boucheva, K., Burleigh, J.E., Thomas, V.H. Drug Metab. Dispos. (2002) [Pubmed]
  9. Characterization of the effects of tebufelone on hepatic cytochromes P450 in the beagle dog. Smith, B.J., Zupan, L.A., Hu, J.K., Diters, R.W., Gibson, G.W., Norton, J.N. Drug Metab. Dispos. (1996) [Pubmed]
  10. Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs. Kyokawa, Y., Nishibe, Y., Wakabayashi, M., Harauchi, T., Maruyama, T., Baba, T., Ohno, K. Chem. Biol. Interact. (2001) [Pubmed]
  11. Comparative analysis of in vitro and in vivo pharmacokinetic parameters related to individual variability of GTS-21 in canine. Azuma, R., Komuro, M., Kawaguchi, Y., Okudaira, K., Hayashi, M., Kiwada, H. Drug Metab. Pharmacokinet. (2002) [Pubmed]
 
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