Post by Max on Jul 5, 2005 8:44:11 GMT -5
Clinical observations of (Ro)accutane induced significant vitamin A deficiency
13-cis-retinoic acid, and all-trans-retinoic acid are vitamin A derivatives used in among other things the treatment of cancer and currently also severe acne. Patients taking these drugs often show side effects resembling the symptoms of hypovitaminosis A (significant vitamin A deficiency) [12 and more]. Vitamin A status plays an important role in reducing infectious disease morbidity and mortality by enhancing immunity, an effect that is partly mediated by macrophages [15]. Other revealed functions in studies of vitamin A include cellular differentiation of epithelial tissues, growth, reproduction and vision [17]. Retinoid metabolism has also been found to take place in several parts of the human brain [18 and more].
Suggested (Ro)accutane induced inhibition of kidney function, significantly decreased uptake of RBP and retinol
Plasma retinol-binding protein (RBP) combined with vitamin A (retinol) is partially filtered through the glomerulus and then absorbed by proximal tubule cells, leading to recycling of retinol to the circulation. Reabsorption of RBP-retinol complexes by proximal tubule cells is mediated by megalin (gp 330), an apical endocytic receptor [4]. Analysis of mice with target disruption of the gene for a major endocytic receptor of proximal tubules, megalin, revealed no RBP in proximal tubules of these mice. Western blotting and HPLC of the urine of the megalin-deficient mice instead revealed a highly increased urinary excretion of RBP and retinol, demonstrating that glomerular filtered RBP-retinol of megalin-deficient mice escapes uptake by proximal tubules [1].
It is well established that the kidney plays an essential role in regulating the homeostasis of body fluids. Evidence shows a significant role of the kidney to be an important organ for the regulation in the metabolism of both fat (vitamin A, D) and water soluble vitamins (e.g. vitamin B12). This regulation is mediated by glomerular filtration as well as reabsorption and secretion processes of protein-bound vitamins. Vitamin transport proteins such as retinol-binding protein, vitamin D-binding protein and transcobalamin II are filtered in renal glomeruli and subsequently reabsorbed in the proximal tubules by endocytosis from the tubular fluid. Megalin, a scavenger receptor belonging to the LDL receptor family, is probably the most important receptor in this process in the proximal tubule cells [2]. A significant deficiency of vitamin A after a (Ro)accutane exposure in human subjects is here suggested, partly due to difficulties with absorbtion of retinol binding protein (RBP).
(Ro)accutane induced inhibition of vitamin A metabolism
Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, are competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4 [3]. At micromolar concentrations, 13-cis retinoic acid also was found to inhibit intestinal lecithin-retinol acyltransferase (LRAT) and to a lesser extent liver LRAT and intestinal retinal reductase [12].
Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of retinal to retinoic acid (RA). In the RALDH1 promoter region of rat kidney cells, TATA and CCAAT cis-acting elements as well as SP1, AP1 and octamer (Oct)-binding sites were present. The CCAAT box and Oct-binding site, located between positions -72 and -68 and -56 and -49, respectively, were shown by deletion analysis and site-directed mutation to be critical for promoter activity. Nuclear extracts from kidney cells contain proteins specifically binding the Oct and CCAAT sequences, resulting in the formation of six complexes, while different patterns of complexes were observed with non-kidney cell extracts [16].
Inhibition of formation of Pyridine diNucleotides through inhibition of Sp1, Sp3, and Egr-1 mediated transcription of PRS - vitamin A metabolism is a downstream target
One of the metabolic pathways that has an absolute requirement for pyridine dinucleotides is the conversion of retinol (vitamin A) to its physiologically active derivative retinoic acid (RA1). Pyridine dinucleotides are found in mitochondria, in the intracellular membranes, associated with both faces of the plasma membrane, in the cytosol, and in the nucleus. Biosynthesis of RA involves reversible dehydrogenation of retinol to retinaldehyde followed by irreversible oxidation of retinaldehyde to retinoic acid. All of the enzymes that can potentially contribute to the production of RA require at least one form of pyridine dinucleotides as a co-substrate, some can utilize all four dinucleotides, albeit with different efficiencies. Because the pyridine dinucleotide pools are not uniformly distributed across organelles, the activities of RA synthesizing enzymes can be substantially influenced by the availability of pyridine dinucleotides within the relevant sub-cellular compartments. In keratinocyte microsomes the conversion of retinol to retinaldehyde depends on NADP and is regulated by the ratio between its oxidized and reduced forms [9].
Phosphoribosylpyrophosphate(PRPP) synthetase(PRS) catalyzes the formation of PRPP from ATP and ribose-5-phosphate. PRPP is an important substrate for the synthesis of purine, pyrimidine, and pyridine dinucleotides. Human PRS exists as complex aggregates composed of the 34 kDa catalytic subunits(PRS1 and PRS2) and other 39 kDa component designated PRPP synthetase-associated protein (PAP39) [11]. Three C(2)H(2) zinc finger proteins, namely Sp1, Sp3, and Egr-1, bind to PRS [10].
13-cis-retinoic acid, and all-trans-retinoic acid are vitamin A derivatives used in among other things the treatment of cancer and currently also severe acne. Patients taking these drugs often show side effects resembling the symptoms of hypovitaminosis A (significant vitamin A deficiency) [12 and more]. Vitamin A status plays an important role in reducing infectious disease morbidity and mortality by enhancing immunity, an effect that is partly mediated by macrophages [15]. Other revealed functions in studies of vitamin A include cellular differentiation of epithelial tissues, growth, reproduction and vision [17]. Retinoid metabolism has also been found to take place in several parts of the human brain [18 and more].
Suggested (Ro)accutane induced inhibition of kidney function, significantly decreased uptake of RBP and retinol
Plasma retinol-binding protein (RBP) combined with vitamin A (retinol) is partially filtered through the glomerulus and then absorbed by proximal tubule cells, leading to recycling of retinol to the circulation. Reabsorption of RBP-retinol complexes by proximal tubule cells is mediated by megalin (gp 330), an apical endocytic receptor [4]. Analysis of mice with target disruption of the gene for a major endocytic receptor of proximal tubules, megalin, revealed no RBP in proximal tubules of these mice. Western blotting and HPLC of the urine of the megalin-deficient mice instead revealed a highly increased urinary excretion of RBP and retinol, demonstrating that glomerular filtered RBP-retinol of megalin-deficient mice escapes uptake by proximal tubules [1].
It is well established that the kidney plays an essential role in regulating the homeostasis of body fluids. Evidence shows a significant role of the kidney to be an important organ for the regulation in the metabolism of both fat (vitamin A, D) and water soluble vitamins (e.g. vitamin B12). This regulation is mediated by glomerular filtration as well as reabsorption and secretion processes of protein-bound vitamins. Vitamin transport proteins such as retinol-binding protein, vitamin D-binding protein and transcobalamin II are filtered in renal glomeruli and subsequently reabsorbed in the proximal tubules by endocytosis from the tubular fluid. Megalin, a scavenger receptor belonging to the LDL receptor family, is probably the most important receptor in this process in the proximal tubule cells [2]. A significant deficiency of vitamin A after a (Ro)accutane exposure in human subjects is here suggested, partly due to difficulties with absorbtion of retinol binding protein (RBP).
(Ro)accutane induced inhibition of vitamin A metabolism
Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, are competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4 [3]. At micromolar concentrations, 13-cis retinoic acid also was found to inhibit intestinal lecithin-retinol acyltransferase (LRAT) and to a lesser extent liver LRAT and intestinal retinal reductase [12].
Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of retinal to retinoic acid (RA). In the RALDH1 promoter region of rat kidney cells, TATA and CCAAT cis-acting elements as well as SP1, AP1 and octamer (Oct)-binding sites were present. The CCAAT box and Oct-binding site, located between positions -72 and -68 and -56 and -49, respectively, were shown by deletion analysis and site-directed mutation to be critical for promoter activity. Nuclear extracts from kidney cells contain proteins specifically binding the Oct and CCAAT sequences, resulting in the formation of six complexes, while different patterns of complexes were observed with non-kidney cell extracts [16].
Inhibition of formation of Pyridine diNucleotides through inhibition of Sp1, Sp3, and Egr-1 mediated transcription of PRS - vitamin A metabolism is a downstream target
One of the metabolic pathways that has an absolute requirement for pyridine dinucleotides is the conversion of retinol (vitamin A) to its physiologically active derivative retinoic acid (RA1). Pyridine dinucleotides are found in mitochondria, in the intracellular membranes, associated with both faces of the plasma membrane, in the cytosol, and in the nucleus. Biosynthesis of RA involves reversible dehydrogenation of retinol to retinaldehyde followed by irreversible oxidation of retinaldehyde to retinoic acid. All of the enzymes that can potentially contribute to the production of RA require at least one form of pyridine dinucleotides as a co-substrate, some can utilize all four dinucleotides, albeit with different efficiencies. Because the pyridine dinucleotide pools are not uniformly distributed across organelles, the activities of RA synthesizing enzymes can be substantially influenced by the availability of pyridine dinucleotides within the relevant sub-cellular compartments. In keratinocyte microsomes the conversion of retinol to retinaldehyde depends on NADP and is regulated by the ratio between its oxidized and reduced forms [9].
Phosphoribosylpyrophosphate(PRPP) synthetase(PRS) catalyzes the formation of PRPP from ATP and ribose-5-phosphate. PRPP is an important substrate for the synthesis of purine, pyrimidine, and pyridine dinucleotides. Human PRS exists as complex aggregates composed of the 34 kDa catalytic subunits(PRS1 and PRS2) and other 39 kDa component designated PRPP synthetase-associated protein (PAP39) [11]. Three C(2)H(2) zinc finger proteins, namely Sp1, Sp3, and Egr-1, bind to PRS [10].
