Drugs and Scaffold That Inhibit Cytochrome P450 27A1 In Vitro and In Vivo

Lam, Morrie; Mast, Natalia; Pikuleva, Irina A.

doi:10.1124/mol.117.110742

Cited by 23 publications

(20 citation statements)

References 40 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(Cuesta de Juan et al 2007;Liu et al 2014) CYP27A1 is sensitive to inhibition by many xenobiotics. (Lam et al 2018) In the present study, the CYPs responsible for cholesterol metabolism and bile acid homeostasis followed "Pattern 2", that was low at the neonatal stage, remained relative high levels throughout the adulthood, and decreased at 800 days of age.…”

Section: P450-7 Family and Ba Homeostasissupporting

confidence: 48%

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

Xie

et al. 2019

Preprint

View full text Add to dashboard Cite

Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1-4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by Western-blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, 5 nuclear receptors, and 4 phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.

show abstract

Section: P450-7 Family and Ba Homeostasissupporting

confidence: 48%

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

Xie

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Such an effect could be due to DMHCA inhibition of CYP27A1 and/or CYP46A1 in C57BL/6J mice, and thus a lack of cholesterol removal by metabolism in the retina of both genotypes. Hence, we used purified recombinant CYP27A1 and CYP46A1 and tested DMHCA for >75% enzyme inhibition in the in vitro enzyme assay, an indication of a strong P450 inhibitor ( Lam et al, 2018 ). Neither CYP27A1 nor CYP46A1 were inhibited by DMHCA in vitro ( Table 3 ), thus suggesting that retinal metabolism of cholesterol does not contribute to retinal cholesterol reduction as a result of DMHCA treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Product formation was linear with time and P450 concentration. More than 75% of inhibition of the P450 activity in this enzyme assay is indicative of a strong inhibitor ( Mast et al, 2012 ; Lam et al, 2018 ).…”

Section: Methodsmentioning

confidence: 91%

“…CYP27A1 and CYP46A1 were evaluated for cholesterol 27- and 24-hydroxylation, respectively. The conditions for each enzyme assay were as described ( Mast et al, 2012 ; Lam et al, 2018 ). For each P450, the cholesterol concentration was equal to 0.5 K m for cholesterol (2.3 and 2.7 μM for CYP27A1 and CYP46A1, respectively) ( Mast et al, 2008 , 2015 ), and DMHCA concentrations were equal to 45 and 43 μM for CYP27A1 and CYP46A1, respectively.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

N,N-Dimethyl-3β-hydroxycholenamide Reduces Retinal Cholesterol via Partial Inhibition of Retinal Cholesterol Biosynthesis Rather Than its Liver X Receptor Transcriptional Activity

et al. 2018

Self Cite

View full text Add to dashboard Cite

N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is an experimental pharmaceutical and a steroidal liver X receptor (LXR) agonist, which does not induce undesired hepatic lipogenesis. Herein, DMHCA was evaluated for its retinal effects on normal C57BL/6J and Cyp27a1−/−Cyp46a1−/− mice; the latter having higher retinal total and esterified cholesterol in addition to retinal vascular abnormalities. Different doses and two formulations were used for DMHCA delivery either via drinking water (C57BL/6J mice) or by oral gavage (Cyp27a1−/−Cyp46a1−/− mice). The duration of treatment was 1 week for C57BL/6J mice and 2 or 4 weeks for Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, the higher DMHCA doses (37–80 mg/kg of body weight/day) neither increased serum triglycerides nor serum cholesterol but altered the levels of retinal sterols. Total retinal cholesterol was decreased in the DMHCA-treated mice, mainly due to a decrease in retinal unesterified cholesterol. In addition, retinal levels of cholesterol precursors lanosterol, zymosterol, desmosterol, and lathosterol were changed in Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, DMHCA effect on retinal expression of the LXR target genes was only moderate and gender-specific. Collectively, the data obtained provide evidence for a decrease in retinal cholesterol as a result of DMHCA acting in the retina as an enzyme inhibitor of cholesterol biosynthesis rather than a LXR transcriptional activator. Specifically, DMHCA appears to partially inhibit the cholesterol biosynthetic enzyme Δ24-dehydrocholesterol reductase rather than upregulate the expression of LXR target genes involved in reverse cholesterol transport. The identified DMHCA dosages, formulations, and routes of delivery as well as the observed effects on the retina should be considered in future studies using DMHCA as a potential therapeutic for age-related macular degeneration and diabetic retinopathy.

show abstract

“…Cedazo-Minguez and co-workers [63] have suggested inhibiting CYP27A1, the enzyme responsible for converting cholesterol to 26-HC may be a preventative strategy to reduce the risk of dementia or to improve therapies to restore neuronal function. Significantly, many existing pharmaceuticals have been shown to have inhibitory effects on CYP27A1 [64], indicating potential new treatments for AD.…”

Section: Neurodegenerative Disease Including Amyotrophic Lateral Sclementioning

confidence: 99%

Oxysterol research: a brief review

Griffiths

Wang

2019

Biochemical Society Transactions

View full text Add to dashboard Cite

In the present study, we discuss the recent developments in oxysterol research. Exciting results have been reported relating to the involvement of oxysterols in the fields of neurodegenerative disease, especially in Huntington's disease, Parkinson's disease and Alzheimer's disease; in signalling and development, in particular, in relation to Hedgehog signalling; and in cancer, with a special focus on (25R)26-hydroxycholesterol. Methods for the measurement of oxysterols, essential for understanding their mechanism of action in vivo, and valuable for diagnosing rare diseases of cholesterol biosynthesis and metabolism are briefly considered.

show abstract

Drugs and Scaffold That Inhibit Cytochrome P450 27A1 In Vitro and In Vivo

Cited by 23 publications

References 40 publications

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

N,N-Dimethyl-3β-hydroxycholenamide Reduces Retinal Cholesterol via Partial Inhibition of Retinal Cholesterol Biosynthesis Rather Than its Liver X Receptor Transcriptional Activity

Oxysterol research: a brief review

Contact Info

Product

Resources

About