Differential regulation of cytochrome P450 3A1 and P450 3A2 in rat liver following dexamethasone treatment.
Induction of P450 3A1 and P450 3A2 was studied in adult rat liver following treatment with a single high dose of dexamethasone (DEX). The increase of both P450 3A1 and 3A2 occurred at the level of mRNA as well as protein. P450 3A isozymes thus induced were catalytically active. No constitutive expression of P450 3A1 mRNA or protein was observed in males or females. Constitutive expression of P450 3A2 mRNA and protein was observed in males but not in females. Additionally, in females, P450 3A2 was almost nondetectable compared to that in males, at any dose of DEX. A time course study following DEX treatment showed that P450 3A1 mRNA and protein were detectable in both sexes at 12 hours, increased until 48 hours, and then declined. The decline was more rapid in males. P450 3A2 mRNA and protein increased as early as 3 hours, increased further up to 48 hours, and slowly declined thereafter. A dose-response study indicated that P450 3A1 mRNA and protein progressively increased in both sexes from a dose of 30 mg/kg. In contrast, P450 3A2 mRNA and protein in males did not increase up to a dose of 30 mg/kg but increased at higher doses. Total P450 content and P450 3A catalytic activity were also found to increase with time and dose.
Choudhuri
S
S
Laboratory for Cancer Research, Rutgers University, Piscataway, NJ 08855, USA.
Zhang
X J
XJ
Waskiewicz
M J
MJ
Thomas
P E
PE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A