Characterization of cytochrome P450‐mediated drug metabolism in cats

Abstract

In this study we examined activities of cytochrome P450 (CYP)1A, 2C, 2D and 3A using hepatic microsomes from five male and five female cats. CYP1A, 2C, 2D and 3A activities were referred by ethoxyresorufin O-deethylation (EROD), tolbutamide hydroxylation (TBH), bufuralol 1'-hydroxylation (BLH) and midazolam 1'- and 4-hydroxylation respectively. The anti-rat CYP1A2 and CYP3A2 serum significantly inhibited EROD and midazolam 1'- and 4-hydroxylation, suggesting that EROD and midazolam 1'- and 4-hydroxylation were catalysed by CYP1A and 3A in cats respectively. Quinidine inhibited BLH in cats microsomes at quite low concentrations, suggesting that BLH was catalysed by CYP2D in cats. Tolbutamide hydroxylation activities were negligible in hepatic microsomes from both male and female cats, suggesting CYP2C activities of cats are extremely low. This suggests that CYP2C substrates should be carefully administered to cats. Although there is no sexual difference in CYP1A activities, there are differences in CYP2D and 3A activities of cats. CYP2D activities were higher (3-fold), but CYP3A activities were lower (one-fifth) in female cats. These results might suggest that CYP2D and 3A substrates should be prescribed for male and female cats using different dosage regimen.

Expression of Two Novel Cytochrome P450 3A131 and 3A132 in Liver and Small Intestine of Domestic Cats

“…There was no clear sex-difference in the hepatic expression of CYP3A131 [male 21.85 ± 7.50 (n=5), female 38.45 ± 6.47 (n=6): arbitrary unit/µg total RNA]. In contrast, hepatic microsomal CYP3A-like activities tend to be higher in female cats than in male cats [11]. CYP3A132 expression in male liver was also not significantly different from that in female liver [male 0.15 ± 0.03 (5), female 0.41 ± 0.27 (6): arbitrary unit/µg total RNA].…”

“…This is partly because of deficiency of enzymes that participate in phenol glucuronidation [2]. Enzymatic activities of CYP3A-like protein, as well as CYP1A, 2B, 2C, 2D and 2E, were characterized in hepatic microsomes of domestic cats, using substrates specific for humans or fluorescent substrates with combination of human prototypical inhibitors to CYP species [11,16]. CYP2A-like and other CYP activities in cat liver microsomes have been also studied with substrates specific for humans to be compared with CYP activities in other mammals [1,10].…”

Molecular Cloning and Expression of Cytochrome P450 2D6 in the Livers of Domestic Cats

“…It is well known that cats are very sensitive to chemicals, and this is partly because of a deficiency of glucuronidation [2]. Among the few reports on feline CYPs, Shah et al [8] characterized CYP1A-, 2C-, 2D-and 3A-dependent enzymatic activities in domestic cats using liver microsomes. Feline CYP2A and CYP2E have been studied with typical human CYP substrates to compare their metabolic activity with CYPs from other mammals [1,6].…”

“…The corresponding amino acid residues (Thr107, Arg296 and Ser486 in the human form) are also replaced with Tyr, Cys and Val in domestic dogs (positions 110, 299 and 489) [7,11]. An in vitro study of CYP2D activities in microsomes of cat liver based on bufuralol 1'-hydroxylation, which was inhibited by quinidine, suggested relatively higher intrinsic clearance than that by the human liver on one hand [8,13] and that the CYP2D6 activities of feline liver microsomes are comparable to those of the human liver and almost twofold higher than those of the canine liver on the other, as Fig. 1.…”

“…Numbers on the tree represent the local bootstrap values from 1,000 replicates. CYP2D isoforms were selected according to Zanger et al [15] expression of CYP2D by sex, although it has been reported that CYP2D activities were higher in hepatic microsomes of female cats [8]. This issue should be further studied with greater numbers of samples as well as samples from other breeds of cats before a final conclusion is drawn.…”