Induction of "male-specific" cytochrome P450 isozymes in female rats by oxandrolone.
Oxandrolone (OXA) (5 alpha-androstan-2-oxa-17 alpha-methyl-17 beta-ol-3-one) is a clinically useful, synthetic, anabolic androgen steroid hormone. OXA was administered to rats orally twice daily for 3 days at 75 mg/kg to study the effect on hepatic cytochrome P450 (P450) isozymes. Western blots were performed on the hepatic microsomal fraction and probed with isozyme-specific monoclonal antibodies. Microsomes were also tested for catalytic activity in a testosterone metabolism assay. Data from Western blots revealed that, in female rats, there were increased levels of two male-specific isozymes, P4502C11 and P4503A2, as well as P4503A1. In contrast, male rats showed little or no change in expression of these P450 isozymes after OXA treatment. The 6 beta-hydroxylation of testosterone, which is catalyzed predominantly by P4503A1 and P4503A2, increased approximately 10-fold in female rats after treatment with OXA (from 0.05 +/- 0.01 to 0.52 +/- 0.05 nmol/min/mg protein), but only relatively small changes were seen in the male rats (from 1.02 +/- 0.05 to 1.38 +/- 0.07 nmol/min/mg protein). To investigate if the changes seen in P4503A1 and P4503A2 protein and activity were caused, at least in part, by an increase in mRNA levels, Northern blot analysis was performed. P4503A2 mRNA was increased dramatically in the female rat liver after OXA treatment, but only small increases in P4503A1 mRNA were seen. This data indicate that OXA induces P450 isozymes in the female but not in the male rat liver, probably through transcriptional activation, and some of these induced isozymes are male-specific.
Waskiewicz
M J
MJ
Department of Toxicology, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789, USA.
Choudhuri
S
S
Vanderbeck
S M
SM
Zhang
X J
XJ
Thomas
P E
PE
D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015342:DNA Probes; D004790:Enzyme Induction; D005260:Female; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D010074:Oxandrolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013739:Testosterone / Q000378:metabolism
D045930:Anabolic Agents; D015342:DNA Probes; D007527:Isoenzymes; D013739:Testosterone; D010074:Oxandrolone; D003577:Cytochrome P-450 Enzyme System