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E T Morgan

Publications and source records attributed to E T Morgan.

60 records · Page 4Linked to original sources
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Effects of vanadate on hepatic cytochrome P-450 expression in streptozotocin-diabetic rats.

The ability of sodium metavanadate to reverse the effects of streptozotocin-induced diabetes on hepatic cytochrome P-450 isozymes was examined in male rats. Streptozotocin caused P-450h levels to fall 95%, and P-450j and P-450b levels to rise 8- and 40-fold, respectively, after 1 week. When diabetic rats were administered metavanadate in the drinking water for 7 days, P-450h apoprotein and mRNA levels remained no different from those of untreated diabetic rats, whereas levels of P-450b and P-450j decreased toward those of control rats. Metavanadate also lowered serum triglyceride and 3-hydroxybutyrate levels without lowering serum glucose in the diabetic rats. Furthermore, P-450h mRNA levels correlated well with levels of P-450h apoprotein for all treatment groups, indicating that P-450h suppression in diabetic rats is under pretranslational control and is independent of the increased expressions of P-450j and P-450b, and of the hyperlipidemia and ketosis that occurs in diabetes. Vanadate is capable of separating the effects of diabetes on expression of individual P-450 isozymes.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Pretranslational suppression of cytochrome P-450h (IIC11) gene expression in rat liver after administration of interferon inducers.

Administration of the interferon inducer polyriboinosinic acid.polyribocytidylic acid (poly rl.poly rC) (10 mg/kg, ip) to male rats suppressed the constitutive hepatic expression of the male-specific cytochrome P-450 [AH, reduced-flavoprotein/oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] isozyme P450IIC11 (P-450h) to 21% of control levels within 24 hr. The mRNA for P-450h was more rapidly suppressed by the drug, being significantly suppressed to 56% of control values within 6 hr of administration. P-450h mRNA levels were further lowered to 10% of control by 24 hr. The kinetics of suppression of P-450h apoprotein and mRNA by poly rl.poly rC indicate that the primary mechanism(s) is (are) at a pretranslational level. Tilorone analog R11-877DA (TA) (50 mg/kg, ip), also an interferon inducer, produced qualitatively similar effects to those of poly rl.poly rC, although the TA produced lesser (51% and 59%) decreases in P-450h protein and mRNA, respectively, 24 hr after injection. Again, the results indicate a pretranslational mechanism of P-450h suppression. Although both interferon inducers suppressed hepatic P-450h expression, the magnitudes of these effects were not notably greater than those on total hepatic P-450, indicating that suppression of rat liver P-450 isozymes by interferon inducers is not confined to P-450h.

Animals↗
PubMedDate not supplied

Effects of cytochrome b5 on cytochrome P-450-catalyzed reactions. Studies with manganese-substituted cytochrome b5.

The effects of cytochrome b5 with manganese-protoporphyrin IX substituted for heme were compared with those of native cytochrome b5 and the apoenzyme on the oxygenation of substrates in the reconstituted system containing liver microsomal cytochrome P-450, NADPH-cytochrome P-450 reductase, and phosphatidylcholine. Mn-b5, unlike b5, remains essentially fully oxidized in the presence of NADPH and NADPH-cytochrome P-450 reductase under aerobic conditions. The effects of various concentrations of b5 and its derivatives were determined at constant P-450 and reductase concentrations. Cytochrome b5 inhibits benzphetamine demethylation by isozyme 2, the effect increasing up to the highest concentrations tested, and stimulates 7-ethoxycoumarin deethylation by isozyme 2 and acetanilide p-hydroxylation by isozyme 4, the optimal b5:P-450 molar ratio being about 2. In contrast, Mn-b5 inhibits all three reactions and apo-b5 is either inactive or slightly inhibitory. The activities of the three substrates as well as testosterone were determined with P-450 isozymes 2, 3b, 3c, and 4 in the reconstituted system with no additions or with b5 or Mn-b5 present. Cytochrome b5 is stimulatory, inhibitory, or without any effect, the result depending on both the substrate and P-450 isozyme present, whereas Mn-b5 is inhibitory in most instances. Both b5 and its manganese derivative alter the rates of testosterone 6 beta- or 16 alpha-hydroxylation by most of the P-450 cytochromes. The activities are influenced by the molar ratio of reductase to P-450. The Km values of benzphetamine, ethoxycoumarin, and acetanilide are, with one exception, significantly decreased in the presence of b5 or Mn-b5. We conclude that some of the effects of b5 on the oxygenase system are not accounted for by its role as an electron donor to cytochrome P-450.

Animals↗