Estrogenic and antiandrogenic activities of 17 benzophenone derivatives used as UV stabilizers and sunscreens

Suzuki, Tomoharu; Kawa, Shigeyuki; Khota, Ryuki; Sugihara, Kazumi; Fujimoto, Nariaki; Ohta, Shigeru

doi:10.1016/j.taap.2004.07.005

Cited by 335 publications

(178 citation statements)

References 28 publications

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“…Several variations of the test protocol exist. The test is usually performed on peri-pubertal male castrated rats Suzuki et al, 2005). For assessment of androgenicity, test compounds are administered to castrated males, while for anti-androgenicity, test compounds are given to castrated, testosterone-treated animals.…”

Section: Testing Estrogenicity Testing Estrogenicity Testing Estrogenmentioning

confidence: 99%

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

Saarinen

Bingham²,

Lorenzetti

et al. 2006

Genes Nutr

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Section: Testing Estrogenicity Testing Estrogenicity Testing Estrogenmentioning

confidence: 99%

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

Saarinen

Bingham²,

Lorenzetti

et al. 2006

Genes Nutr

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“…An inhibitory effect of benzophenones on CYP51 has not to our knowledge been reported previously. However, hydroxybenzophenones, including DHBP, have been found elsewhere to inhibit squalene cyclase, another enzyme in cholesterol biosynthesis (67), and have been identified as estrogen receptor ligands exhibiting estrogenic and antiandrogenic activities in a human breast cancer cell line (68,69). Further, a biochemical evaluation of nonsteroidal benzophenone-containing analogs of cholesterol suggests that the benzophenone scaffold can successfully replace the sterol tetracyclic nucleus in apolipoprotein-dependent cellular sterol efflux (70).…”

Section: Discussionmentioning

confidence: 99%

“…The 4-hydroxyl group of DHBP, which is essential for hormonal activities of benzophenone derivatives (69), mimics the sterol C-3 hydroxyl group in the active site of CYP51 Mt . Two DHBP 4-hydroxyphenyl rings positioned in an angular arrangement contact the same amino acid residue as the tetracyclic estriol (Fig.…”

Section: Discussionmentioning

confidence: 99%

X-ray Structure of 4,4′-Dihydroxybenzophenone Mimicking Sterol Substrate in the Active Site of Sterol 14α-Demethylase (CYP51)

Eddine

Kries²,

Podust

et al. 2008

Journal of Biological Chemistry

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A universal step in the biosynthesis of membrane sterols and steroid hormones is the oxidative removal of the 14␣-methyl group from sterol precursors by sterol 14␣-demethylase (CYP51). This enzyme is a primary target in treatment of fungal infections in organisms ranging from humans to plants, and development of more potent and selective CYP51 inhibitors is an important biological objective. Our continuing interest in structural aspects of substrate and inhibitor recognition in CYP51 led us to determine (to a resolution of 1.95 Å ) the structure of CYP51 from Mycobacterium tuberculosis (CYP51 Mt ) cocrystallized with 4,4-dihydroxybenzophenone (DHBP), a small organic molecule previously identified among top type I binding hits in a library screened against CYP51 Mt . The newly determined CYP51 Mt -DHBP structure is the most complete to date and is an improved template for three-dimensional modeling of CYP51 enzymes from fungal and prokaryotic pathogens. The structure demonstrates the induction of conformational fit of the flexible protein regions and the interactions of conserved Phe-89 essential for both fungal drug resistance and catalytic function, which were obscure in the previously characterized CYP51 Mt -estriol complex. DHBP represents a benzophenone scaffold binding in the CYP51 active site via a type I mechanism, suggesting (i) a possible new class of CYP51 inhibitors targeting flexible regions, (ii) an alternative catalytic function for bacterial CYP51 enzymes, and (iii) a potential for hydroxybenzophenones, widely distributed in the environment, to interfere with sterol biosynthesis. Finally, we show the inhibition of M. tuberculosis growth by DHBP in a mouse macrophage model.2 is a cytochrome P450 (P450, CYP) heme thiolate containing enzyme involved in biosynthesis of membrane sterols, including cholesterol in animals, ergosterol in fungi, and a variety of C24-modified sterols in plants and protozoa in most organisms in biological kingdoms from bacteria to animals (1). CYP51 has been a therapeutic target for several generations of azole antifungal agents including fluconazole, voriconazole, itraconazole, ravuconazole, and posaconazole (2). These drugs inhibit microbial growth by disrupting biosynthesis of ergosterol, a major component of fungal membrane. Protozoa share with fungi the requirement of ergosterol and ergosterol-related sterols for cell viability and proliferation (3). Inhibition of sterol biosynthesis has been proven to be effective in trypanosomatids (3-5) and Leishmania spp (6), which cause such tropical diseases as African sleeping sickness, Chagas disease, and leishmaniasis.Although mammalian CYP51 enzymes perform the same catalytic reaction (7) as their fungal and protozoan orthologs (1), they share relatively modest overall sequence identity (within 30%) with them. This accounts for the reduced sensitivity of mammalian CYP51 to azole and triazole drugs. Despite the lack of the full sterol biosynthetic pathway in Mycobacterium tuberculosis (8), and hence, de novo sterol biosynthesis...

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“…Some insecticides and medicines are also possible proestrogens. Hydroxylated derivatives of sunscreen, 88) and phthalate esters 89) show positive in estrogenicity tests. Thus, the parent compounds may be proestrogens.…”

Section: Activation Of Other Proestrogens In Environments By the Cytomentioning

confidence: 99%

Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

Kawa

Sugihara

Sanoh

et al. 2008

JOURNAL OF HEALTH SCIENCE

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Liver microsome-mediated activation of proestrogens in the environment is reviewed here. Proestrogens such as methoxychlor, trans-stilbene, diphenyl, diphenylmethane, 2,2-diphenylpropane, benzo[a]pyrene, benzophenone, 2-nitrofluorene (NF), chalcone, trans-4-phenyl-3-buten-2-one and styrene oligomers are negative in in vitro estrogen screening tests. However, those proestrogens exhibit estrogenic activity after metabolic activation by the microsomal cytochrome P450 system. In these cases, hydroxylated derivatives of the compounds are formed as major metabolites, and these metabolites exhibit significant estrogenic activities. Thus, the estrogenic activities of proestrogenic compounds are a consequence of metabolism of the parent compounds. Various candidates for proestrogens among medicines and insecticides are also discussed.

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Estrogenic and antiandrogenic activities of 17 benzophenone derivatives used as UV stabilizers and sunscreens

Cited by 335 publications

References 28 publications

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

X-ray Structure of 4,4′-Dihydroxybenzophenone Mimicking Sterol Substrate in the Active Site of Sterol 14α-Demethylase (CYP51)

Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

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