Characterization of cytochrome P450 (CYP3A12) induction by rifampicin in dog liver.
1. Effects of rifampicin (Rif) on the contents of cytochrome P450 (P450) enzymes (CYP1A1/2, 2B11, 2C21 and 3A12) assessed by enzyme-linked immunosorbent assay and catalytic activities (ethoxyresorufin O-deethylase, and testosterone 6 beta-, 16 alpha- and 16 beta-hydroxylase; 6 beta-, 16 alpha- and 16 beta-OHT) in dog liver microsomes were compared between liver lobes of both the male and female dogs. 2. In the control dogs, the contents of individual P450 enzymes and their activities showed no significant differences between individual liver lobes and between the sexes. 3. Rif treatment (10 mg/kg/day, p.o. for 7 days) induced substantial increases in the content of CYP3A12 and 6 beta- and 16 beta-OHT activities, and slight increases in the content of CYP2B11 and 16 alpha-OHT activity, and their elevated levels were virtually the same between liver lobes. The magnitudes of the elevation of the CYP3A12 level and 6 beta- and 16 beta-OHT activities compared with control levels appeared to be greater in the female dogs. However, the ratios of their magnitudes (CYP3A content/6 beta-OHT activity and CYP3A content/16 beta-OHT activity) showed no differences between the sexes. 4. In both the control and Rif-treated dogs, the activities of 6 beta- and 16 beta-OHT were specifically inhibited by anti-CYP3A12 antiserum, and 16 alpha-OHT activity was specifically inhibited by anti-CYP2B11 and anti-CYP2C21 antiserum. 5. These results indicate that Rif treatment induces the expression of CYP3A12 protein, and correlates well with the elevation of its catalytic activity (6 beta- and 16 beta-OHT), and that the female dog is more responsive to Rif treatment as compared with the male.
Nishibe
Y
Y
Developmental Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan.
Wakabayashi
M
M
Harauchi
T
T
Ohno
K
K
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D012293:Rifampin / Q000494:pharmacology*; D012727:Sex Characteristics; D013250:Steroid Hydroxylases
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000072467:Cytochrome P450 Family 2; C090278:cytochrome P-450 CYP2B11 (dog); C475779:cytochrome P-450 CYP3A12 (canine); D012293:Rifampin