Comparison of hamster and mouse reveals interspecies differences in the regulation of hepatic CYP2A isozymes.
Three CYP2A-related activities [coumarin 7-hydroxylase (COH), testosterone 7 alpha- (test7 alpha) and 15 alpha-hydroxylases (test15 alpha)], identified in hamster liver and analysed by immunoinhibition, and western and northern blotting, were found to be similar to mouse and human CYP2As. In the microsomal fractions, anti-mouse CYP2A5 antibody recognised three bands of about 48, 49 and 52 kDa, suggesting the presence of at least three proteins immunologically similar to mouse CYP2A5. The 49 kDa band migrated close to mouse CYP2A5 and changes in its expression followed COH and test15 alpha activities. Test7 alpha activity did not associate with any of the individual bands detected on western blots despite its strong inhibition by the antibody. Despite the immunological and catalytic similarities between mouse and hamster CYP2A enzymes, their regulation is different. In mice, the enzyme activities are higher in females than males, are induced by pyrazole (PY) and phenobarbital (Pb), and are not affected by 3-methylcholanthrene (MC). In hamsters, activities are not higher in females, induced by MC and reduced by PY. MC and PY appear to regulate expression at the mRNA level, while Pb seems to act post-transcriptionally by increasing either the synthesis or the stability of the protein. Our data indicate that the modes of expression and regulation of CYP2A-related enzymes make the hamster different from mice and humans with respect to the mechanism of metabolism of certain drugs and carcinogens.
Pelkonen
P
P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Honkakoski
P
P
Geneste
O
O
Bartsch
H
H
Lang
M A
MA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015153:Blotting, Western; D006224:Cricetinae; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000276:immunology; D000072467:Cytochrome P450 Family 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; C050356:steroid 15-alpha-hydroxylase