INDUCIBILITY OF CYTOCHROMES P-450 BY DIOXIN IN LIVER AND EXTRAHEPATICTISSUES OF THE MARMOSET MONKEY (CALLITHRIX-JACCHUS)

Cytochrome P-450 induction was investigated in the marmoset monkey, a non-human primate, using dioxins as inducing agents. Animals received a single subcutaneous dose of 1.6 nmol tetrachlorodibenzo-p-dioxin or tetrabromodibenzo-p-dioxin/kg body weight. Microsomal fractions were p repared from liver, lung and kidney, and homogenates were prepared fro m gut and adrenal glands. Anti-peptide antibodies which bind to CYP1A1 , CYP1A2, CYP2B6 and CYP3A4 in human were used to identify related for ms in the marmoset. The results indicate that CYP1A2 is constitutively expressed in liver, but not in lung, kidney, gut or adrenal gland and that CYP1A1 is not expressed in any of these tissues in untreated ani mals. Treatment with dioxin induced both CYP1A1 and CYP1A2 in liver, b ut only CYP1A1 in lung. No induction of CYP1A1 or CYP1A2 was found in kidney, small intestine or adrenal glands. Methoxy-, ethoxy-, pentoxy- and benzoyloxyresorufin O-dealkylases and high affinity phenacetin O- deethylase activities were induced in the liver, whereas ethoxycoumari n O-deethylase and aryl hydrocarbon hydroxylase activities were not af fected by dioxin treatment. High-affinity phenacetin O-deethylase and CYP1A2 apoprotein were detected only in liver, consistent with this ac tivity being specifically catalysed by CYP1A2. Furafylline was found t o be a competitive inhibitor of methoxyresorufin O-demethylase activit y with a K-i of 10 mu M. In the lung the induction of CYP1A1 was accom panied by 15- and 23-fold increases in ethoxyresorufin O-deethylase an d methoxyresorufin O-demethylase activities, respectively, suggesting that both activities are catalysed by CYP1A1. In contrast, there was n o induction of aryl hydrocarbon hydroxylase activity in lung or liver showing that, unlike in many other species, marmoset CYP1A1 does not c atalyse this reaction efficiently. The expression, distribution, induc tion and substrate specificities of marmoset monkey P-450 enzymes diff er from the situation found in rodents and other species, demonstratin g that caution has to be exercised when making cross-species extrapola tions.