Disease relevance of CYP3A12

• Escherichia coli expression and substrate specificities of canine cytochrome P450 3A12 and rabbit cytochrome P450 3A6 [1].

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

• CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation [5].
• 6. All dog livers expressed mRNA and CYP3A12, CYP2B11, CYP2C21 proteins, with no sex differences being found [6].

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

• In both control and Rif-treated dogs, immunoblotting of intestinal microsomes with anti-CYP3A12 antiserum produced a band indistinguishable from that of purified CYP3A12 or of immunoreactive CYP3A12 in liver microsomes [10].
• Third, we quantified the contents of CYP1A and CYP3A12 by enzyme-linked immunosorbent assay [11].

References