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DIFFERENCES IN P450 EXPRESSION IN A RAT MODEL OF THE DEBRISOQUINE 4-HYDROXYLASE POLYMORPHISM
SAEED SAEED ALGHAMDI
Abstract
The purpose of this study was to investigate the level of expression of the P450 enzymes
CYP1A2, CYP2C12, CYP2C13, CYP3A1, CYP3A2 and CYP2E1 in the liver of male and
female Dark Agouti (DA), Sprague-Dawley (SD) and Wistar rats. This was achieved by
immunoquantitation by dot blotting using highly specific antibodies against each P450
enzyme. Sex differences in the level of expression of CYP2C13, CYP3A1 and CYP3A2
were found. Higher levels of these P450 enzymes were found in male rats, although the
difference varied between the 3 strains of rat. In DA, Wistar and SD rats, CYP2C13 was
increased by 70-, 17- and 4-fold, respectively, CYP3A1 was increased by 3-, 3-, and 2-fold,
respectively, and CYP3A2 increased by 100-, 10- and 8-times, respectively. Strain
differences in the level of expression of these enzymes was also found. Male DA had a
higher level of expression of CYP2C13 than SD (9-fold) or Wistar rats (6-fold), although in
female the level was higher in Wistar compared with DA rats (3-fold). Both male Wistar and
DA rats had a higher level of CYP3A1 than SD rats (2-3fold). Male DA and SD rats also
had a higher levels of CYP3A2 than Wistar rats (3-4 fold), and in female SD rats had a
higher level than the other strains of rat (4-8 fold). The data produced indicated that
CYP2C12 was expressed to a higher level in male as well as female rats. This unexpected
result may due to a lack of specificity of the antibody used, possibly bind to CYP2C22 and
other CYP2C forms. In contrast to other P450 enzymes, no sex or strain variation in the
level of expression of CYP1A2 and CYP2E1 was found. It is concluded from this study that
immunoquantification using dot blotting was successful and demonstrated differences in the
levels of several P450 enzymes between sexes and strains. This variation important
implication in the use of different rat strains studying drug metabolism.
Pages:48
SAEED SAEED ALGHAMDI
Abstract
The purpose of this study was to investigate the level of expression of the P450 enzymes
CYP1A2, CYP2C12, CYP2C13, CYP3A1, CYP3A2 and CYP2E1 in the liver of male and
female Dark Agouti (DA), Sprague-Dawley (SD) and Wistar rats. This was achieved by
immunoquantitation by dot blotting using highly specific antibodies against each P450
enzyme. Sex differences in the level of expression of CYP2C13, CYP3A1 and CYP3A2
were found. Higher levels of these P450 enzymes were found in male rats, although the
difference varied between the 3 strains of rat. In DA, Wistar and SD rats, CYP2C13 was
increased by 70-, 17- and 4-fold, respectively, CYP3A1 was increased by 3-, 3-, and 2-fold,
respectively, and CYP3A2 increased by 100-, 10- and 8-times, respectively. Strain
differences in the level of expression of these enzymes was also found. Male DA had a
higher level of expression of CYP2C13 than SD (9-fold) or Wistar rats (6-fold), although in
female the level was higher in Wistar compared with DA rats (3-fold). Both male Wistar and
DA rats had a higher level of CYP3A1 than SD rats (2-3fold). Male DA and SD rats also
had a higher levels of CYP3A2 than Wistar rats (3-4 fold), and in female SD rats had a
higher level than the other strains of rat (4-8 fold). The data produced indicated that
CYP2C12 was expressed to a higher level in male as well as female rats. This unexpected
result may due to a lack of specificity of the antibody used, possibly bind to CYP2C22 and
other CYP2C forms. In contrast to other P450 enzymes, no sex or strain variation in the
level of expression of CYP1A2 and CYP2E1 was found. It is concluded from this study that
immunoquantification using dot blotting was successful and demonstrated differences in the
levels of several P450 enzymes between sexes and strains. This variation important
implication in the use of different rat strains studying drug metabolism.
Pages:48
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