Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression?
The higher systemic clearance of some CYP3A4 [whether also P-glycoprotein (P-gp)] drug substrates in women versus men is attributed in part to a higher hepatic CYP3A4 content in women. This, combined with the general paucity of reported sex differences in the apparent oral clearance of CYP3A4 substrates, suggested a sex-dependent expression of CYP3A4 in the intestine, but in a pattern opposite to that in the liver. Accordingly, duodenal biopsies obtained from healthy men (n = 46) and women (n = 45) were analyzed, by Western blot, for relative CYP3A4, as well as for CYP3A5 and P-gp, expression levels. Among all subjects, CYP3A4 and P-gp varied 8- and 10-fold, respectively. CYP3A5, which was readily detected in 27% of these predominantly white individuals, varied 7-fold. For all three proteins, a sex difference was not detected (p >/= 0.55). The lack of a difference remained for CYP3A4 and P-gp when the analysis was restricted to white individuals (n = 74) or to individuals with undetectable CYP3A5. Comparing the 21 premenopausal women (all were aged <45 years) with the 43 men aged <45 years, again no sex differences were detected in CYP3A4 and P-gp. Comparing the pre- with postmenopausal women, mean CYP3A4 content was 20% lower in the postmenopausal individuals (p = 0.01). The lack of a sex-dependent difference in proximal intestinal CYP3A4 could account, in part, for the lack of reported sex differences in the oral, relative to systemic, clearance of some CYP3A4 substrates. Ramifications of lower intestinal CYP3A4 content in post- versus premenopausal women require further investigation.
Paine
Mary F
MF
General Clinical Research Center, Room 3005, Bldg. APCF, CB# 7600, UNC Hospitals, Chapel Hill, NC 27599-7600, USA. mpaine@med.unc.edu
Ludington
Shana S
SS
Chen
Mei-Ling
ML
Stewart
Paul W
PW
Huang
Shiew-Mei
SM
Watkins
Paul B
PB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004386:Duodenum / Q000201:enzymology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012737:Sex Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human