Vitamin D analogues targeting CYP24 in chronic kidney disease

Posner, Gary H.; Helvig, Christian; Cuerrier, Dominic; Collop, Drew; Kharebov, Aza Z.; Ryder, Kara; Epps, Tina; Petkovich, Martin

doi:10.1016/j.jsbmb.2010.03.065

Cited by 46 publications

(57 citation statements)

References 23 publications

(27 reference statements)

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“…Another commercial company, Cytochroma Inc., has also developed inhibitors to vitamin-D-related CYPs based upon a vitamin D template and tuning out the VDR-binding properties [123]. Several of these molecules, including CTA-018, are under development as CYP24A1 inhibitors for potential clinical use in CKD, psoriasis, and cancer [124]. All of these vitamin-D-related CYP inhibitors are usually specific enough for use as single-purpose drugs and rarely inhibit other unrelated CYPs and occasionally trigger VDR-mediated gene transcription.…”

Section: Inhibitors Of Vitamin-d-related Cyp Enzymesmentioning

confidence: 99%

The Activating Enzymes of Vitamin D Metabolism (25- and 1α-Hydroxylases)

Jones

Prosser

2011

Vitamin D

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Section: Inhibitors Of Vitamin-d-related Cyp Enzymesmentioning

confidence: 99%

The Activating Enzymes of Vitamin D Metabolism (25- and 1α-Hydroxylases)

Jones

Prosser

2011

Vitamin D

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“…It has been demonstrated that mice have a relatively higher sensitivity to adenine-induced toxicity than rats. Rats tolerate dietary levels of adenine at 0.75% for prolonged periods (8 weeks or more) [9,11,19,22] Figure 3. Histology of sliced/ H&E stained kidneys from selected groups in murine adenine-induced kidney insufficiency studies.…”

Section: Discussionmentioning

confidence: 99%

“…Supplemental calcitriol (active vitamin D) is known to increase phosphate absorption [6,7,19]. The goal of experiment 2 was to determine the interaction of active vitamin D and adenine on phosphate metabolism during renal dysfunction (Table 2).…”

Section: Methodsmentioning

confidence: 99%

Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Bobeck¹,

Piccione²,

Bishop³

et al. 2017

Nephrol Renal Dis

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Hyperphosphatemia in chronic kidney disease (CKD) patients is a risk factor for cardiovascular events, progressive kidney failure, and mortality. Improved therapeutic interventions to control hyperphosphatemia depend greatly on robust animal models that recapitulate the CKD disease process. Murine-based models of CKD as compared to rat models present significant advantages due to available genetic knockout lines that permit mechanistic dissection of CKD etiologies. The rat adenine model of renal failure has been extensively studied, and studies are now emerging describing adenine-induced renal failure in murine models. However, these newly developed murine models have not fully described the responses to calcitriol and phosphate binders, and the reported effects of adenine on serum phosphate is often lacking in murine models. Therefore, the objectives of this study were: 1) To induce hyperphosphatemia in mice using adenine with minimal mortality, and 2) Report the influence of calcitriol and phosphate binders on the disease process through measurement of serum phosphate and histology. In one approach, C57BL/6 male mice gavaged with 4 or 6 mg adenine/day, as compared to 0 mg adenine/day developed hyperphosphatemia, with low mortality. In a second approach, calcitriol exacerbated adenine-induced increases in serum phosphate at day 7 of adenine administration (p<0.05). Notably, adenine treated mice had 4-fold increased stomach weights vs. non-adenine treated mice (p<0.0001). The addition of a phosphate binder (experiment 3, sevelamer hydrochloride) was ineffective at preventing an adenine-induced increase in blood phosphate, a finding that likely resulted from adenine's inhibition of gastric emptying. We report the successful use of adenine to induce hyperphosphatemia, that the hyperphosphatemic status is exacerbated by calcitriol, and a limitation of the model for studying oral therapies for hyperphosphatemia.

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“…As CYP24A1 inactivates pro-hormonal, hormonal, and analog forms of vitamin D, the aberrant elevation in CYP24A1 expression may contribute to vitamin D insufficiency and exacerbate SHPT in CKD patients. These novel findings suggest that treatment of CKD patients might be another clinical management situation that could benefit from the availability of specific inhibitors of CYP24A1 [123].…”

Section: Cyp24a1 In Chronic Kidney Diseasementioning

confidence: 96%

“…As part of the effort to chemically synthesize vitamin D analogs with low calcemic activity, potent inhibitors of CYP24A1 based on the 1,25(OH) 2 D secosteroid structure were identified [123]. These include sulfone [152] and sulfoximine [44] derivatives of 1,25(OH) 2 D. The 16,23-diene-25 sulfone analog (compound CTA018/MT2832) [123] is particularly interesting from a therapeutic standpoint as it exhibits a dual mechanism of action.…”

Section: Cyp24a1 Inhibitorsmentioning

confidence: 99%

Cyp24a1

St‐Arnaud

2011

Vitamin D

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Vitamin D analogues targeting CYP24 in chronic kidney disease

Cited by 46 publications

References 23 publications

The Activating Enzymes of Vitamin D Metabolism (25- and 1α-Hydroxylases)

The Activating Enzymes of Vitamin D Metabolism (25- and 1α-Hydroxylases)

Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Cyp24a1

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