Comparison of the Stimulatory and Inhibitory Effects of Steroid Hormones and α-Naphthoflavone on Steroid Hormone Hydroxylation Catalyzed by Human Cytochrome P450 3A Subfamilies

Abstract

The inhibitory and stimulatory effects of steroid hormones and related compounds on the hydroxylation activity at the 6β-position of two steroid hormones, progesterone and testosterone, by CYP3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared to clarify the catalytic properties of the predominant forms of the human CYP3A subfamily. Hydroxylation activities of progesterone and testosterone by CYP3A4, CYP3A5, and CYP3A7 were estimated using HPLC. The Michaelis constants (K m ) for progesterone 6β-hydroxylation by CYP3A5 were markedly decreased in the presence of dehydroepiandrosterone (DHEA) and α-naphthoflavone (ANF), whereas progesterone and DHEA competitively inhibited testosterone 6β-hydroxylation mediated by CYP3A4, and progesterone competitively inhibited CYP3A5-mediated activity, which was weaker than that for CYP3A4. ANF noncompetitively inhibited testosterone 6β-hydroxylation mediated by both CYP3A4 and CYP3A5. Progesterone and testosterone 6β-hydroxylation mediated by CYP3A7 was inhibited or unaffected by DHEA, pregnenolone, and ANF. These results suggested that DHEA and ANF stimulated progesterone 6β-hydroxylation by CYP3A5 but not by CYP3A4 and CYP3A7; however, progesterone, DHEA, and ANF inhibited testosterone 6β-hydroxylation mediated by all CYP3A subfamily members. The inhibitory/stimulatory pattern of steroid-steroid interactions is different among CYP3A subfamily members and CYP3A5 is the most sensitive in terms of activation among the CYP3A subfamily members investigated.

Flavonoids as CYP3A4 Inhibitors In Vitro

“…The effectiveness of acacetin, chrysin, and α-naphthoflavone should be singled out. The remaining enzyme activity in these cases was 5 ± 4%, 17 ± 3%, and 6.8% [ 115 , 116 ].…”

Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine

“…Unfortunately, there has been a lack of well-designed studies on PROG-drug interactions. In addition, the possible effects of genetic polymorphisms of CYP3A4 and SULT2A1 on PROG metabolism should be considered [ 132 , 133 , 134 , 135 ].…”

The Role of CYP3A in Health and Disease

“…In this context, testosterone stimulates progesterone 6β-hydroxylation, whereas progesterone inhibits CYP3A-mediated 6β-hydroxylation of testosterone [ 226 ]. Cortisone is also metabolized to 6β-hydroxycortisone by CYP3A enzymes [ 227 , 228 ].…”

“…2β-, 15β- and 16β-hydroxylation of testosterone is mediated by CYP3A4 [ 227 , 229 ]. The formation of 6β- and 2β-hydroxytestosterone is catalyzed by CYP3A5 and CYP3A7, while 2α-hydroxytestosterone generation is catalyzed only by CYP3A7 [ 228 , 230 ].…”

“…In addition, CYP3A4, CYP3A5 and CYP3A7 metabolize estrone to form 2-, 4- and 16α-hydroxylated metabolites [ 234 , 235 , 236 , 237 ]. Progesterone is metabolized by CYP3A4 to form 2β-, 6β-, 16α- and 21-hydroxylated metabolites, as well as CYP3A5 and CYP3A7 to form 6β-hydroxyprogesterone [ 226 , 227 ].…”