Sexual differentiation and regulation of cytochrome P-450 CYP2C7.
The multigene family of proteins known as the cytochrome P-450-dependent monooxygenases play a central role in the metabolism of hormones and foreign compounds. As part of our studies into the function and regulation of these proteins we have isolated a little studied constitutively expressed isozyme CYP2C7 and have investigated its substrate specificity and mode of regulation. Interestingly the haem of this enzyme in its isolated form is almost 100% in the high spin state. The enzyme was active in the metabolism of a range of model resorufin substrates, but exhibits highest activity towards benzyloxyresorufin. Indeed, this isozyme appears to play a significant role in the metabolism of this substrate in microsomal samples from untreated male rats. Tissue distribution studies indicated that CYP2C7 was expressed in liver, kidney and possibly muscle tissue. Cytochrome P-450 CYP2C7 could not be significantly induced by any of a wide range of known modulators of cytochrome P-450 expression at the mRNA level, however some significant changes in protein expression were observed. Some of the agents used (e.g., diethylnitrosamine and carbon tetrachloride) caused a significant reduction in the expression of this protein. In agreement with other reports where mRNA levels were measured we found that the level of CYP2C7 protein expression was sexually differentiated. Female rats express two to three times the level found in males, the sex difference being reversible by hypophysectomy.
Imperial Cancer Research Fund, Molecular Pharmacology Group, Edinburgh, U.K.
C J
CJ
Henderson
A L
AL
Russell
J A
JA
Allan
C R
CR
Wolf
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D003429:Cross Reactions; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007016:Hypophysectomy; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D005810:Multigene Family; D010078:Oxazines / Q000378:metabolism; D012313:RNA / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012733:Sex Differentiation; D013057:Spectrum Analysis; D013379:Substrate Specificity
D002273:Carcinogens; D007527:Isoenzymes; D010078:Oxazines; D012313:RNA; C014180:resorufin; D004247:DNA; D003577:Cytochrome P-450 Enzyme System