P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 alpha-hydroxylase of dehydroepiandrosterone 3-sulfate.

Kitada, Munehiro; Kamataki, Tetsuya; Itahashi, Koshiro; Rikihisa, Tadaaki; Kanakubo, Yoshio

doi:10.1016/s0021-9258(19)76460-6

Cited by 147 publications

(15 citation statements)

References 29 publications

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“…Compared to CYP3A4/5, the catalytic efficiency of CYP3A7 with most substrates is significantly reduced, as evident from the substantially lower V max and higher K m values [ 12 , 13 ] ( Table 1 ). Metabolic activity of CYP3A7 is greater only with two natural substrates, DHEAS [ 9 , 32 ] and atRA [ 10 ], suggesting the evolutionary role of CYP3A7 in embryonic development and protection against DHEAS/atRA-induced embryotoxicity, teratogenicity, and premature birth. However, even DHEAS, atRA, and other typical CYP3A substrates do not induce feasible high-spin transition in CYP3A7 ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…Significant levels of CYP3A7 can also be found in other fetal tissues, as well as in developing infants up to 24 months post-gestational age (reviewed in [ 7 ]). The main function of CYP3A7 during fetal development is regulation of placental estriol synthesis via 16α-hydroxylation of dihydroepiandrosterone (DHEA) and its sulfate derivative (DHEAS) [ 8 , 9 ], as well as clearance of all-trans retinoic acid (atRA) [ 10 ], the primary ligand for embryonic nuclear retinoic acid receptors. During the first week after birth, CYP3A7 expression progressively declines, while CYP3A4 expression is simultaneously activated through transcriptional regulation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7

Sevrioukova

2021

IJMS

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Cytochrome P450 3A7 (CYP3A7) is a fetal/neonatal liver enzyme that participates in estriol synthesis, clearance of all-trans retinoic acid, and xenobiotic metabolism. Compared to the closely related major drug-metabolizing enzyme in adult liver, CYP3A4, the ligand binding and catalytic capacity of CYP3A7 are substantially reduced. To better understand the structural basis for these functional differences, the 2.15 Å crystal structure of CYP3A7 has been solved. Comparative analysis of CYP3A enzymes shows that decreased structural plasticity rather than the active site microenvironment defines the ligand binding ability of CYP3A7. In particular, a rotameric switch in the gatekeeping amino acid F304 triggers local and long-range rearrangements that transmit to the F-G fragment and alter its interactions with the I-E-D-helical core, resulting in a more rigid structure. Elongation of the β3-β4 strands, H-bond linkage in the substrate channel, and steric constraints in the C-terminal loop further increase the active site rigidity and limit conformational ensemble. Collectively, these structural distinctions lower protein plasticity and change the heme environment, which, in turn, could impede the spin-state transition essential for optimal reactivity and oxidation of substrates.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7

Sevrioukova

2021

IJMS

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“…This could point to a mechanism that may explain many of the clinical pathologies associated with Kaletra treatment. However, ritonavir and lopinavir are much more effective inhibitors of CYP3A4, the CYP enzyme predominantly associated with their clearance in vivo , than other CYP enzymes. ,− Interestingly, CYP3A4 is virtually absent in the neonate, while CYP3A7 is the dominant CYP3A subfamily enzyme present and is responsible for the clearance of drugs through the CYP3A enzymatic pathway. − Nevertheless, the primary role of CYP3A7 is the oxidation of DHEA-S to 16α-hydroxydehydroepiandrosterone 3-sulfate (16α-hydroxy DHEA-S), , an important intermediate in the estriol biosynthetic pathway. In the pregnant mother, 16α-hydroxy DHEA-S is exported to the placenta where it subsequently undergoes desulfation and a series of oxidations to ultimately form estriol, which is critically important in bringing the pregnancy to full term. , Women with low estriol levels are far more likely to give birth to premature and even stillborn infants .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Kandel

Lampe

2021

Chem. Res. Toxicol.

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Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC 50 = 0.0514 μM), while lopinavir is a much weaker inhibitor (IC 50 = 5.88 μM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a K I of 0.392 μM and a k inact of 0.119 min –1 , illustrating the potential for CYP3A mediated drug–drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.

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“…18,19) Furthermore, the ratio of 6β-hydroxycortisol to cortisol in urine or plasma is proposed as an in vivo endogenous marker of CYP3A4 metabolic activity. [20][21][22] CYP3A5 and CYP3A7 as well as CYP3A4 catalyze the oxidation of various compounds, including the 6β-and 16α-hydroxylation of endogenous steroid hormones such as testosterone, cortisol, and dehydroepiandrosterone (DHEA). 10,23,24) We recently compared the enzymatic kinetic parameters, such as K m and k cat values, for the 6β-hydroxylation of progesterone, testosterone, and cortisol mediated by CYP3A4, CYP3A5, and CYP3A7.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22] CYP3A5 and CYP3A7 as well as CYP3A4 catalyze the oxidation of various compounds, including the 6β-and 16α-hydroxylation of endogenous steroid hormones such as testosterone, cortisol, and dehydroepiandrosterone (DHEA). 10,23,24) We recently compared the enzymatic kinetic parameters, such as K m and k cat values, for the 6β-hydroxylation of progesterone, testosterone, and cortisol mediated by CYP3A4, CYP3A5, and CYP3A7. 25,26) We previously found that steroid hormones, such as progesterone, testosterone, and α-naphthoflavone (ANF), stimulate CYP3A4-mediated metabolism, including nifedipine oxidation and/or 7-benzyloxyresorufin O-debenzylation.…”

Section: Introductionmentioning

confidence: 99%

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

Niwa

Toyota

Kawasaki

et al. 2021

Biological & Pharmaceutical Bulletin

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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.

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P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 alpha-hydroxylase of dehydroepiandrosterone 3-sulfate.

Cited by 147 publications

References 29 publications

Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7

Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

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

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