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What is known and objective: Favipiravir is a promising treatment candidate for managing coronavirus disease 2019 (COVID‐19). Warfarin has many drug interactions, but no interactions with favipiravir have been reported. Case summary: Our patient was taking warfarin for deep vein thrombosis. The international normalized ratio (INR) was stable (1.65 to 2.0); however, it increased to 4.63 after administering favipiravir. The patient had no other factors justifying this change. What is new and conclusion: Favipiravir and warfarin might have previously unidentified drug interactions that elevated the INR. Therefore, INR must be closely monitored when they are concomitantly administered in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5 mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of > 370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382. [ABSTRACT FROM AUTHOR]

Abstract: Docking and molecular dynamics (MD) simulation have been two computational techniques used to gain insight about the substrate orientation within protein active sites, allowing to identify potential residues involved in the binding and catalytic mechanisms. In this study, both methods were combined to predict the regioselectivity in the binding mode of valproic acid (VPA) on three cytochrome P-450 (CYP) isoforms CYP2C9, CYP2C11, and CYP2E1, which are involved in the biotransformation of VPA yielding reactive hepatotoxic intermediate 2-n-propyl-4-pentenoic acid (4nVPA). There are experimental data about hydrogen atom abstraction of the C4-position of VPA to yield 4nVPA, however, there are not structural evidence about the binding mode of VPA and 4nVPA on CYPs. Therefore, the complexes between these CYP isoforms and VPA or 4nVPA were studied to explore their differences in binding and energetic stabilization. Docking results showed that VPA and 4nVPA are coupled into CYPs binding site in a similar conformation, but it does not explain the VPA hydrogen atom abstraction. On the other hand, MD simulations showed a set of energetic states that reorient VPA at the first ns, then making it susceptible to a dehydrogenation reaction. For 4nVPA, multiple binding modes were observed in which the different states could favor either undergo other reaction mechanism or ligand expulsion from the binding site. Otherwise, the energetic and entropic contribution point out a similar behavior for the three CYP complexes, showing as expected a more energetically favorable binding free energy for the complexes between CYPs and VPA than with 4nVPA. [Copyright &y& Elsevier]

Abstract: The incidence of nontuberculous mycobacteria (NTM) has increased over the last decades. Elderly people are more susceptible to NTM and experience increased morbidities. NTM incidence is expected to rise due to an increasing elderly population at least up to 2050. Given the importance of NTM infection in the elderly, an increasing interest exists in studying NTM characteristics in the aged population. In this review, we summarize the characteristics of NTM infection among elderly patients. We focus on epidemiology, clinical presentation, and treatment options of NTM in this age group. We highlight the differences in the diagnosis and treatment between rapid and slow growing mycobacterial infections. The current recommendation for treatment of NTM is discussed. We debate if in vitro susceptibility testing has a role in the treatment of NTM. Drug–drug interaction between antibiotics used to treat NTM and other medications, particularly warfarin, is another important issue that we discuss. Finally, we review the prognosis of NTM disease in elderly patients. [Copyright &y& Elsevier]

Highlights: [•] Ferulic acid is a phenolic acid endowed with strong antioxidant and cytoprotective activities. [•] Ferulic acid’s low bioavailability is a limit for the clinical use of this compound. [•] Ferulic acid’s protective effects depend mainly on its direct scavenger activity towards free radicals. [•] Ferulic acid is also able to up-regulate cytoprotective systems and down-regulate cytotoxic ones. [•] Due to several mechanisms of action, ferulic acid could be a potential adjuvant treatment for free radical-induced diseases. [ABSTRACT FROM AUTHOR]

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Abstract: DAX1 is an orphan nuclear receptor with actions in mammalian sex determination, regulation of steroidogenesis, embryonic development and neural differentiation. Conserved patterns of DAX1 gene expression from mammals to fish have been taken to suggest conserved function. In the present study, the European sea bass, Dicentrarchus labrax, DAX1 promoter was isolated and its conserved features compared to other fish and mammalian DAX1 promoters in order to derive common regulators and functional gene networks. Fish and mammalian DAX1 promoters share common sets of transcription factor frameworks which were also present in the promoter region of another 127 genes. Pathway analysis clustered these into candidate gene networks associated with the fish and mammalian DAX1. The networks identified are concordant with described functions for DAX1 in embryogenesis, regulation of transcription, endocrine development and steroid production. Novel candidate gene network partners were also identified, which implicate DAX1 in ion homeostasis and transport, lipid transport and skeletal development. Experimental evidence is provided supporting roles for DAX1 in steroid signalling and osmoregulation in fish. These results highlight the usefulness of the in silico comparative approach to analyse gene regulation for hypothesis generation. Conserved promoter architecture can be used also to predict potentially new gene functions. The approach reported can be applied to genes from model and non-model species. [Copyright &y& Elsevier]

Abstract: Hypertension is an important risk factor for kidney failure and renal events in the general population. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with profound analgesic and anti-inflammatory effects, resulting from its ability to activate peroxisome proliferator activated receptor (PPAR)α. A role for this nuclear receptor has been addressed in cardiovascular system and PPARα ligands have been shown to protect against inflammatory damage especially resulting from angiotensin II hypertension. In this study, we demonstrated that PEA significantly reduced blood pressure in spontaneously hypertensive rats (SHR) and limited kidney damage secondary to high perfusion pressure. To investigate the mechanisms involved in PEA effect, we found that PEA reduced cytochrome P450 (CYP) hydroxylase CYP4A, epoxygenase CYP2C23 and soluble epoxide hydrolase enzyme expression in the kidney, accompanied by a reduction of 20-hydroxyeicosatetraenoic acid excretion in the urine. Moreover, it markedly reduced kidney oxidative and nitrosative stress accompanied by decreased expression of renal NAD(P)H oxidase and inducible nitric oxide synthase and increased expression of Cu/Zn superoxide dismutase, in the kidney of SHR. Moreover, angiotensin II receptor (AT) evaluation revealed a decrease in AT1 receptor expression and a restoration of AT2 receptor level in the kidney from PEA-treated SHR. Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis. These results indicate that PEA treatment lowers blood pressure and can protect against hypertensive renal injury by increasing the antioxidant defense and anti-inflammatory response and modulating renin-angiotensin system. [Copyright &y& Elsevier]

Highlights: [•] Aflatoxins and ochratoxin A are the more widespread mycotoxins. [•] The exposure to DON and to the sum of T2+HT2 toxins can be moderate in the European countries. [•] Some special population groups can be over-exposed to several mycotoxins. [ABSTRACT FROM AUTHOR]

Abstract: Allele frequency differences of functional CYP2C9 polymorphisms are responsible for some of the variation in drug response observed in human populations. The most relevant CYP2C9 functional variants are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). These polymorphisms show variation in allele frequencies among different population groups. The present study aimed to analyze these polymorphisms in 947 Mexican-Mestizo from Mexico City and 483 individuals from five indigenous Mexican populations: Nahua, Teenek, Tarahumara, Purepecha and Huichol. The CYP2C9*2 allele frequencies in the Mestizo, Nahua and Teenek populations were 0.051, 0.007 and 0.005, respectively. As for CYP2C9*3, the allelic frequencies in the Mestizo, Nahua and Teenek populations were 0.04, 0.005 and 0.005, respectively. The CYP2C9*2 and CYP2C9*3 alleles were not observed in the Tarahumara, Purepecha and Huichol populations. These findings are in agreement with previous studies reporting very low allele frequencies for these polymorphisms in American Indigenous populations. [Copyright &y& Elsevier]

Mutagenic 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), formed from norharman and aniline in the presence of S9 mix, is thought to be accountable for the co-mutagenic action of norharman. Our previous studies suggest that cytochrome P-450s (CYPs) are involved in the generation of APNH. In order to identify the responsible CYP species in the present study, norharman (8 mg) and aniline (4 mg) were incubated with individual recombinant human CYPs (2 nmol) at 37 °C for 20 min. Formation of APNH was observed with CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2D6, CYP2E1 and CYP3A4, but not with CYP2A6, CYP2C9 and CYP2C19. The amounts of APNH from norharman and aniline were 33 ng for CYP1A1, 15 ng for CYP3A4, 7 ng for CYP2D6, 6 ng for CYP1A2 and 5 ng for CYP2B6. APNH formation in the presence of CYP1B1 and CYP2E1 was very low at around one fiftieth of that with CYP3A4. When CYP selective chemical inhibitors, such as furafylline for CYP1A2 and ketoconazole for CYP3A4, were added to the reaction mixture of norharman, aniline and human microsomes, formation of APNH was decreased to 14 and 16% of the control level, respectively. Moreover, human lung microsomes also showed the activity of APNH formation from norharman and aniline, albeit at only one hundredth of that with liver microsomes. In general, content in human liver microsomes is rather high for CYP3A4 and CYP1A2 but relatively low for CYP2D6 and CYP2B6, at about 30, 10, 1.5% and less than 1% of the total CYP, respectively. Although CYP1A1 showed the highest APNH formation activity, its expression in human liver is reported to be below the level of detection. Based on these observations, it is suggested that the practical major contributors to the formation of APNH from norharman and aniline are CYP3A4 and CYP1A2, the responsible reactions mainly occurring in the liver. [Copyright &y& Elsevier]

Identification of cytochrome P-450 isoenzymes (CYPs) involved in perazine 5-sulphoxidation and N-demethylation was carried out using human liver microsomes and cDNA-expressed human CYPs (Supersomes). In human liver microsomes, the formation of perazine metabolites correlated significantly with the level of CYP1A2 and ethoxyrezorufin O-deethylase activity, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylperazine also correlated well with S-mephenytoin 4′-hydroxylase activity (CYP2C19). α-Naphthoflavone (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of perazine 5-sulphoxidation, while ticlopidine (a CYP2C19 inhibitor) strongly reduced the rate of perazine N-demethylation in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of perazine metabolites, but the preference of CYP isoforms to catalyze perazine metabolism was as follows (pmol of product/pmol of CYP isoform/min): 1A1>2D6>2C19>1A2>2B6>2E1>2A6≈3A4>2C9 for 5-sulphoxidation and 2C19>2D6>1A1>1A2>2B6>3A4>2C9>2A6 for N-demethylation.In the light of the obtained results and regarding the contribution of each isoform to the total amount of CYP in human liver, it is concluded that CYP1A2 and CYP3A4 are the main isoenzymes catalyzing 5-sulphoxidation (32% and 30%, respectively), while CYP2C19 is the main isoform catalyzing perazine N-demethylation (68%). CYP2C9, CYP2E1 CYP2C19 and CYP2D6 are engaged to a lesser degree in 5-sulphoxidation, while CYP1A2, CYP3A4 and CYP2D6 in perazine N-demethylation (6–10%, depending on the isoform). [Copyright &y& Elsevier]

S-(−)-Nicotine and 13 of the most prevalent nicotine-related alkaloids and metabolites (i.e., S-(−)-nornicotine, myosmine, β-nicotyrine, S-cotinine, S-norcotinine, S-(−)-nicotine N-1′-oxide, S-(−)-nicotine Δ1′–5′-iminium ion, S-(−)-anabasine, S-(−)-N-methylanabasine, anabaseine, S-(−)-anatabine, nicotelline, and 2,3′-bipyridyl) were evaluated as inhibitors of human cDNA-expressed cytochrome P-450 2A6 (CYP2A6) mediated coumarin 7-hydroxylation. Tobacco alkaloids myosmine, S-(−)-nornicotine, S-cotinine, S-norcotinine, S-(−)-nicotine N-1′-oxide, S-(−)-nicotine Δ1′–5′-iminium ion, S-(−)-N-methylanabasine, anabaseine, and nicotelline had Ki values for inhibition of coumarin 7-hydroxylation ranging from 20 μM to more than 300 μM whereas nicotine and S-(−)-anatabine were much more potent (i.e. 4.4 and 3.8 μM, respectively). The tobacco alkaloids 2,3′-bipyridyl (7.7 μM) and S-(−)-anabasine (5.4 μM), were somewhat less potent compared with S-(−)-nicotine or S-(−)-anatabine in inhibition of human CYP2A6. β-Nicotyrine, in which the N-methylpyrrolidino moiety of nicotine was replaced by the aromatic N-methylpyrrole ring, was shown to inhibit human CYP2A6 with much greater potency (Ki=0.37 μM) compared with S-(−)-nicotine. Among the compounds examined, only nicotine and β-nicotyrine were mechanism-based inhibitors of human CYP2A6. The potency of the mechanism-based CYP2A6 inhibitors suggests that, for smokers, modulation of CYP2A6 may be greater than that predicted on the basis of serum concentration of these alkaloids. Our results indicate that the prominent nicotine-related alkaloid β-nicotyrine present after smoking potently inhibits human CYP2A6. [Copyright &y& Elsevier]

Zolmitriptan is a novel and highly selective 5-HT1B/1D receptor agonist used as an acute oral treatment for migraine. There are few reports regarding the in vitro metabolism of zolmitriptan. Previous studies indicated zolmitriptan was metabolized via CYP1A2 in human hepatic microsomes. In order to study the enzyme kinetics and drug interaction, the metabolism of zolmitriptan and possible drug–drug interactions were investigated in rat hepatic microsomes induced with different inducers. An active metabolite, N-demethylzolmitriptan, was detected and another minor, inactive metabolite that was reported in human hepatic microsomes was not detected in this study. The enzyme kinetics for the formation of N-demethylzolmitriptan from zolmitriptan in rat liver microsomes pretreated with BNF were 96±22 μM (Km), 11±3 pmol min−1 mg protein−1 (Vmax), and 0.12±0.02 μl min−1 mg protein−1 (CLint). Fluvoxamine and diphenytriazol inhibited zolmitriptan N-demethylase activity catalyzed by CYP1A2 (Ki=3.8±0.3 and 3.2±0.1 μM, respectively). Diazepam and propranolol elicited a slight inhibitory effect on the metabolism of zolmitriptan (Ki=70±11 and 90±18 μM, respectively). Cimetidine and moclobemide produced no significant effect on the metabolism of zolmitriptan. Fluvoxamine yielded a kinactivation value of 0.16 min−1, and Ki of 57 μM. The results suggest that rat hepatic microsomes are a reasonable model to study the metabolism of zolmitriptan, although there is a difference in the amount of minor, inactive metabolites between human hepatic microsomes and rat liver microsomes. The results of the inhibition experiments provided information for the interactions between zolmitriptan and drugs co-administrated in clinic, and it is helpful to explain the drug–drug interactions of clinical relevance on enzyme level. This study aso demonstrated that fluvoxamine may be a mechanism-based inactivator of CYP1A2. [Copyright &y& Elsevier]

Antioxidant and pro-oxidant effects of 14 naturally occurring polyphenols (PP) on rat liver microsomal lipid peroxidation (LP) and hydroxyl radical (⋅OH) production were studied in NADPH-dependent, 50 μM Fe2+–500 μM ascorbate (Fe–AA) or 50 μM Fe2+ system, respectively. LP determined by the thiobarbituric acid method was inhibited in the NADPH system by flavonols and trans-resveratrol that were more effective than other flavonoids and derivatives of benzoic and cinnamic acid and were mostly more efficient than in the Fe–AA system. Inhibition of LP in the Fe system was higher by one order of magnitude than in the Fe–AA system. ⋅OH production in the NADPH system, measured by formaldehyde production, was decreased by myricetin, fisetin and quercetin, but increased by kaempferol, morin and trans-resveratrol, indicating that ⋅OH played a minor role in LP, which all of these PP inhibited. None of these PP at up to 40 μM concentration quenched ⋅OH in the Fe–AA system. All tested PP, except trans-resveratrol and gentisic acid, spectrally interacted with Fe2+ or Fe3+, indicating formation of complexes or oxidation of PP. In contrast to the NADPH system we found no correlation between Fe2+ chelation and inhibition of Fe–AA- or Fe-dependent LP indicating that iron chelation did not play a significant role in the two latter systems. It is concluded that the inhibition of LP by PP was apparently due to their hydrogen donating properties rather than chelation of iron. [Copyright &y& Elsevier]

UDP-glucuronosyltransferases (UGTs) represent major phase II drug metabolizing enzymes. They are part of a rapidly growing, sequence similarly based superfamily of UDP-glycosyltransferases, including a number of enzymes, which presumably are functionally unrelated to UGTs. The present commentary discusses evolutionary aspects of the large glycosyltransferase superfamily emphasizing functionally related members which share roles in detoxication and elimination of endo- and xenobiotics. The discussion starts with the two human UGT families and polymorphism frequencies in different populations. These families probably evolved in vertebrates as a result of the struggle against toxic phytoalexins at the hepatogastrointestinal barrier. Co-regulation of some UGTs with other drug metabolizing enzymes may also have evolved in the course of ‘animal–plant warfare’. Related UDP-glucosyltransferases evolved in insects. Even in plants and bacteria UDP-glucosyltransferases have been characterized which may be functionally related. [Copyright &y& Elsevier]

Toxicogenomics is the study of the structure and output of the genome as it responds to adverse xenobiotic exposure. Large-scale transcriptional analysis, made possible through microarray technologies, enables us to study and understand the complexity of the biological effects of drugs and chemicals, with the ultimate goal of separating wanted effects from adverse effects. Nuclear receptors are attractive targets for drug discovery because, as ligand-activated transcription factors, they coordinately regulate the expression of at least hundreds of genes that, in turn, control much of cellular metabolism. Through toxicogenomics, it is becoming possible to understand the therapeutic effects of agonists within the context of toxic effects, classify new chemicals as to their complete effects on biological systems, and identify environmental factors that may influence safety or efficacy of new and existing drugs. [Copyright &y& Elsevier]

We first identified the transcriptional regulatory element of the CYP2D4 gene. CYP2D4 is of interest in brain pharmacology and physiology because this enzyme can be involved in the metabolism of endogenous and exogenous compounds, which act on the central nervous system. Transfection studies using a series of the CYP2D4 promoter luciferase constructs identified the transcriptional element of CYP2D4 in the sequence between nucleotides −116 and −90 (named the neural expression regulatory element, NERE). The nucleotide sequence of NERE was specific for the CYP2D4 gene. Within this region, two nuclear factor-binding sequences, Oct-1 and YY-1, were present. Oct-1 acts as the activator of the CYP2D4. The core sequence of the YY-1 binding motif partially overlapped that of the Oct-1 binding motif. YY-1 may act as the repressor of CYP2D4, which interferes with Oct-1 activation by its binding to NERE. We concluded that a novel transcriptional regulatory element NERE specifically regulates the expression of the CYP2D4. This regulation system may be involved in the unique distribution of this isoform, such as the expression in the brain. [Copyright &y& Elsevier]

This paper is one of several prepared under the project “Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet” (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered. [Copyright &y& Elsevier]

The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. Further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is ore toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity. [ABSTRACT FROM PUBLISHER]

Cites a study examining the effects of modified cyclodextrins (CD) hydroxypropyl-β-CD and methyl-β-CD on cDNA-expressed human cytochrome P-450 (CYP) activities. Ability of modified CD to inhibit the activities of CYP2C19 and CYP3A4; Enhancement by CD of the CYP2C9 activity by 140 to 176 percent; Inhibition by methyl-β-CD of CYP1A2 and CYP2D6 at higher concentrations.

Focusing on licorice, a highly used raw material in health foods, quantitative analysis of functional/medicinal components and a safety and functional evaluation was carried out for herbal medicines, health food ingredients, and so-called health foods. A functional component, glabridin, was detected in herbal medicines from Glycyrrhiza glabra and G. inflata , health food ingredients, and in commercially available health foods that contain licorice. Likewise, glycyrrhizin, a medicinal component, was detected in these sources, except in licorice oil extract. Estrogen activity in vitro was detected in some of the herbal medicines, health food ingredients, and in health foods containing licorice. In the in vivo study, liver weight in ovariectomized (OVX) mice treated with licorice oil extract was significantly higher than that in OVX and sham mice in a dose dependent manner. These results suggest that excessive intake of licorice oil extract from health foods should be avoided, even though these ingredients might be beneficial for medical use in order to maintain bone health in postmenopausal women. Measurement of hepatic cytochrome P-450 (CYP) activity, reproductive organ weight, and fat and bone mass in OVX mice was considered useful for evaluating the safety and efficacy of estrogenic health food ingredients derived from herbal medicines., Competing Interests: The authors declare no conflict of interest.