NATURES AID MINI MULTIVITAMIN DROPS (Each ml contains Ascorbic Acid , Nicotinamide, Calcium Panthothenate, Vitamin A Acetate Prep, Vitamin D3 Prep, Thiamine HCL, Pyrodoxine HCL, Riboflavin, Vitamin B12 PRE )

Indications

• Papulopustular rosacea
• Inflammatory acne vulgaris

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: For papulopustular rosacea, apply daily for up to 4 months. The treatment course may be repeated; discontinue if no improvement is observed after 3 months. For inflammatory acne vulgaris, apply twice daily, reduced to once daily or alternate days if irritation occurs.

Mechanism of action

Nicotinamide exhibits anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines and enhancing the barrier function of the skin. It is also involved in the NAD salvage pathway, which is essential for maintaining cellular energy levels and promoting cell repair mechanisms. Additionally, nicotinamide contributes to the synthesis of coenzymes involved in metabolic processes, including the conversion of niacin into NAD+.

Pharmacodynamics

Nicotinamide is known for its ability to improve skin hydration and reduce transepidermal water loss. It has been shown to decrease the appearance of acne lesions and rosacea by modulating inflammatory responses and accelerating cell turnover. Its antioxidant properties also help to protect the skin from oxidative stress and UV damage.

Pharmacokinetics

When applied topically, nicotinamide is absorbed through the skin layers, with minimal systemic absorption. Its peak plasma concentrations are generally low, and the drug has a half-life that varies depending on the route of administration. The metabolism of nicotinamide occurs primarily in the liver, where it is converted into its active forms, including NAD+. The elimination route is via the kidneys, with metabolites excreted in urine.

Contra-indications

• Pregnancy
• Severe acne involving large areas
• Severe skin reactions

Adverse effects

• Sunburn
• Skin reactions (common or very common)
• Cheilitis
• Eyelid oedema
• Flushing
• Dry skin
• Eye irritation
• Photosensitivity reactions
• Transient skin pigmentation changes

Interactions

• Clindamycin
• Topical retinoids
• Abrasive cleaners
• Comedogenic cosmetics

Precautions

• Avoid exposure to UV light, including sunlight and sunlamps
• Wash hands immediately after use
• Avoid contact with eyes and mucous membranes
• Use moisturizers to reduce the risk of skin irritation
• Discontinue treatment if severe irritation occurs

Pregnancy

Avoid use during pregnancy due to potential risks, as limited information is available regarding toxicity.

Breast-feeding

Amount of drug in milk after topical application is probably too small to be harmful; ensure infant does not come in contact with treated areas.

Storage

Store at room temperature away from moisture and light.

Formulations

• Cream
• Gel

Indications

• Vitamin C deficiency
• Scurvy
• Adjunct therapy in iron overload conditions

Dosage

Children: Child 1 month–3 years: 125–250 mg daily in 1–2 divided doses; Child 4–11 years: 250–500 mg daily in 1–2 divided doses; Child 12–17 years: 0.5–1 g daily in 1–2 divided doses.

Adults: 500 mg daily, taken in 1-2 divided doses, depending on the clinical condition and dietary needs.

Mechanism of action

Ascorbic acid functions primarily as a reducing agent, facilitating enzymatic reactions in the body, including the hydroxylation of proline and lysine in collagen synthesis. It also plays a role in the absorption of iron from the gastrointestinal tract and enhances the immune response.

Pharmacodynamics

Ascorbic acid is crucial for the maintenance of connective tissue and is involved in the metabolism of several amino acids. Its antioxidant properties help to mitigate oxidative stress and may play a role in reducing the risk of chronic diseases.

Pharmacokinetics

Ascorbic acid is absorbed in the intestines and is widely distributed throughout the body. The renal clearance of ascorbic acid is dose-dependent, with higher doses leading to increased excretion. The half-life varies but is generally around 15 to 30 minutes in healthy individuals, with tissue saturation levels influencing its retention.

Contra-indications

• Hypercalcaemia
• Hyperoxaluria
• Patients with cardiac dysfunction

Adverse effects

• Abdominal pain
• Headache
• Nausea
• Vomiting
• Diarrhoea
• Constipation
• Weight loss
• Polyuria
• Sweating
• Thirst
• Vertigo

Interactions

• Increases risk of cardiovascular adverse effects with iron chelators
• Increases risk of cardiovascular adverse effects with deferiprone
• Increases risk of cardiovascular adverse effects with desferrioxamine

Precautions

• Use with caution in patients with iron overload
• Monitor for symptoms of overdose

Pregnancy

High doses teratogenic in animals but therapeutic doses unlikely to be harmful.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Ascorbic acid 50 mg tablets
• Ascorbic acid 100 mg tablets
• Ascorbic acid 200 mg tablets
• Ascorbic acid 250 mg tablets
• Ascorbic acid 500 mg capsules

Indications

• Vitamin B2 deficiency
• Isoniazid-induced neuropathy (prophylaxis and treatment)
• Metabolic diseases
• Cystathioninuria
• Homocystinuria
• Wilson's disease
• Prevention of penicillamine-induced neuropathy

Mechanism of action

Riboflavin acts as a precursor to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential coenzymes in various enzymatic reactions. It binds to riboflavin hydrogenase, riboflavin kinase, and riboflavin synthase, facilitating the production of FMN and FAD. These coenzymes are critical for normal tissue respiration and energy metabolism, influencing hydrogen transport in oxidative enzyme systems such as cytochrome C reductase and succinic dehydrogenase. Moreover, riboflavin contributes to the antioxidant activity by aiding in the production of reduced glutathione, a key antioxidant in the body.

Pharmacodynamics

Riboflavin is an easily absorbed, water-soluble micronutrient that supports energy production by assisting in the metabolism of fats, carbohydrates, and proteins. It is vital for red blood cell formation, antibody production, and regulating growth and reproduction. The vitamin plays a significant role in maintaining healthy skin, nails, and hair, as well as supporting thyroid activity. Riboflavin also has therapeutic implications in preventing or treating various eye disorders, including cataracts.

Pharmacokinetics

Riboflavin is rapidly absorbed in the gastrointestinal tract, with its bioavailability influenced by dietary intake. It is primarily excreted through urine, with excess intake leading to bright yellow urine, which is a harmless side effect. The vitamin does not accumulate in the body, necessitating regular dietary intake to maintain adequate levels.

Adverse effects

• Urine discolouration
• Peripheral neuritis

Precautions

• With intravenous use, risk of cardiovascular collapse; resuscitation facilities must be available and monitor closely.

Pregnancy

Crosses the placenta but no adverse effects reported; information at high doses limited.

Breast-feeding

Present in breast milk but no adverse effects reported; information at high doses limited.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• 100 mg modified-release tablets
• 50 mg capsules
• 100 mg capsules
• 100 mg tablets
• Oral solution

Indications

• Vitamin B1 deficiency
• Wernicke-Korsakoff syndrome
• Beriberi
• Isoniazid-induced neuropathy (prophylaxis and treatment)
• Severe depletion or malabsorption of vitamins B and C

Dosage

Adults: For vitamin deficiency: 25–100 mg daily. For severe deficiency: 200–300 mg daily in divided doses. For

Mechanism of action

Thiamine functions primarily as a precursor for several phosphorylated active forms, which act as coenzymes in metabolic pathways. It reduces intracellular protein glycation by redirecting glycolytic flux and supports the synthesis of nucleic acids necessary for cell survival and proliferation. Additionally, thiamine has been shown to inhibit glucose-induced proliferation of endothelial cells, thus possibly playing a role in the modulation of vascular health.

Pharmacodynamics

Thiamine exhibits antioxidant properties and contributes to erythropoiesis, cognitive function, and mood regulation. It has protective effects against oxidative stress, particularly in neuronal tissues, where deficiency can lead to neuronal death due to increased free radical production. Thiamine also modulates glucose metabolism, influencing smooth muscle cell proliferation and potentially impacting the progression of atherosclerosis.

Pharmacokinetics

Thiamine is rapidly absorbed from the gastrointestinal tract, primarily in the jejunum, and is distributed throughout the body, with higher concentrations found in the liver, heart, and brain. It is excreted in urine, and its half-life is relatively short. The vitamin is converted into active forms within tissues, including thiamine diphosphate (TDP), which is the coenzyme form involved in carbohydrate metabolism. The body does not store significant amounts of thiamine, making regular dietary intake essential.

Adverse effects

• Allergic reactions
• Anaphylaxis (rare)
• Gastrointestinal disturbances

Precautions

• Facilities for treating anaphylaxis should be available when parenteral thiamine is administered
• Use with caution in patients with a history of hypersensitivity to thiamine

Pregnancy

Thiamine crosses the placenta but no adverse effects have been reported. Information regarding high doses is limited.

Breast-feeding

Severely thiamine-deficient mothers should avoid breast-feeding as thiamine is present in breast milk.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Thiamine hydrochloride 20 mg/ml oral solution
• Thiamine hydrochloride 50 mg tablets
• Thiamine hydrochloride 100 mg modified-release tablets
• Thiamine hydrochloride oral suspension

Indications

• Pantothenic acid deficiency
• Adjuvant therapy in chronic stress
• Support in metabolic syndromes

Dosage

Children: Refer to established guidelines and consult appropriate literature for specific pediatric dosing recommendations.

Adults: Refer to established guidelines and consult appropriate literature for specific dosing recommendations.

Mechanism of action

Pantothenate serves as a precursor for the synthesis of coenzyme A, which is crucial for the metabolism of fatty acids and the synthesis of lipid-derived hormones. Coenzyme A acts as a carrier of acyl groups in various biochemical pathways, facilitating the transfer of acyl groups to different substrates, thus playing a significant role in the Krebs cycle and fatty acid oxidation.

Pharmacodynamics

Pantothenate is involved in various enzymatic reactions as a part of coenzyme A, enhancing the metabolism of macronutrients. It helps in the synthesis of neurotransmitters and the production of steroid hormones, thereby influencing physiological processes like growth and development, immune response, and energy production.

Pharmacokinetics

Pantothenic acid is absorbed in the intestines through a sodium-dependent active transport mechanism. It is widely distributed throughout the body and is excreted primarily through urine as pantothenic acid and its metabolites. The bioavailability of pantothenate can be affected by gastrointestinal health and the presence of other nutrients.

Adverse effects

• Diarrhea
• Nausea
• Abdominal cramping
• Allergic reactions (rare)

Precautions

• Use with caution in individuals with a known allergy to pantothenic acid or any other components of the formulation.
• Consult healthcare providers before starting supplementation, especially in those with pre-existing medical conditions.

Pregnancy

Pantothenic acid is generally considered safe during pregnancy as it is a water-soluble vitamin essential for human metabolism.

Breast-feeding

Pantothenic acid is excreted in breast milk, and adequate intake during lactation is important for both the mother and infant.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets
• Capsules
• Powder for solution

Indications

• Plant growth regulation
• Pest control in agricultural settings

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Refer to the BNF for specific dosing guidelines based on the application context.

Mechanism of action

Prep acts as a plant growth regulator and organophosphorus pesticide, penetrating plant tissues and decomposing to ethylene. Its activity involves the inhibition of several key enzymes, including acetylcholinesterase and butyrylcholinesterase, leading to disruptions in normal physiological processes in both plants and pests. The bioactivation of organophosphorus compounds often occurs through oxidation at sulfur or nitrogen atoms linked to phosphorus, although some interactions involve different sites on the molecule.

Pharmacodynamics

The pharmacodynamics of Prep involve its systemic penetration into plant tissues, where it influences growth processes through the action of ethylene. As an organophosphorus compound, it exhibits high potency and specificity, acting primarily by phosphorylating various enzymes critical for normal functioning in target organisms. This leads to a disruption in normal growth and metabolic pathways, particularly through enzyme inhibition.

Pharmacokinetics

The pharmacokinetics of Prep involve its absorption into plant systems and subsequent conversion to active metabolites like ethylene. The specific rates of absorption, distribution, metabolism, and excretion in plants are subject to variations based on environmental conditions and plant species.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether this drug is excreted in human milk. Caution should be exercised when administered to a nursing woman.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Pyridoxine deficiency
• Certain types of anemia (e.g., sideroblastic anemia)
• Peripheral neuropathy
• Carpal tunnel syndrome
• Nausea and vomiting in pregnancy (as part of combination therapy)
• As an adjunctive treatment in chronic inflammatory conditions

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations based on the child's age and condition.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated.

Mechanism of action

Pyridoxine is converted in the body to its active form, pyridoxal phosphate, which serves as a coenzyme in more than 100 enzymatic reactions. These reactions primarily involve the metabolism of amino acids, the synthesis of neurotransmitters such as serotonin and dopamine, and the conversion of homocysteine to cysteine, which is important for cardiovascular health.

Pharmacodynamics

The pharmacodynamic effects of pyridoxine are linked to its role in amino acid metabolism and neurotransmitter synthesis. By facilitating the activity of various enzymes, pyridoxine contributes to the regulation of mood, cognitive function, and immune response. Deficiencies in vitamin B6 can lead to symptoms such as irritability, depression, confusion, and peripheral neuropathy due to impaired neurotransmitter production.

Pharmacokinetics

Pyridoxine is absorbed in the small intestine and is widely distributed throughout the body. It is primarily excreted in urine as pyridoxal and pyridoxic acid. The half-life of pyridoxine varies but is generally around 15 to 20 days. The vitamin's bioavailability can be affected by factors such as dietary intake and the presence of certain medications.

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Headache
• Peripheral neuropathy (with high doses)

Interactions

• May interact with isoniazid, leading to decreased effectiveness of pyridoxine
• Chronic use of penicillamine may reduce the effectiveness of pyridoxine

Precautions

• Use with caution in patients with renal impairment
• High doses should be avoided due to the risk of neuropathy

Pregnancy

Pyridoxine is generally considered safe during pregnancy and is often recommended to alleviate nausea and vomiting.

Breast-feeding

Pyridoxine is excreted in breast milk, but at therapeutic doses, it is not expected to harm the infant.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution
• Oral solution

Indications

• Thiamine deficiency
• Wernicke's encephalopathy
• Beriberi
• Alcoholism-related complications
• Certain metabolic disorders

Dosage

Children: Refer to BNF for Children for appropriate dosing information.

Adults: Refer to established clinical guidelines or BNF for specific dosing recommendations.

Mechanism of action

Thiamine is a coenzyme for several important enzymatic reactions, including the pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase. It is essential for converting carbohydrates into energy, facilitating the metabolism of glucose, and maintaining normal nerve function.

Pharmacodynamics

Thiamine deficiency leads to impaired carbohydrate metabolism, which can result in neurological and cardiovascular dysfunction. Supplementation with thiamine helps restore normal metabolic function and can alleviate symptoms associated with deficiency, such as Wernicke's encephalopathy and Beriberi. It also plays a role in the synthesis of neurotransmitters and in maintaining myelin integrity.

Pharmacokinetics

Thiamine is readily absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It is distributed throughout the body, primarily in the liver, kidneys, and heart. Thiamine is metabolized in the liver to its active form, thiamine pyrophosphate. It has a biological half-life of about 9-18 days and is excreted primarily in the urine. Excess thiamine is excreted, making toxicity rare.

Adverse effects

• Allergic reactions
• Hypersensitivity reactions
• Gastrointestinal disturbances

Interactions

• May interact with certain diuretics, leading to altered thiamine levels

Precautions

• Use with caution in patients with renal impairment
• Monitor patients with a history of thiamine deficiency

Pregnancy

Thiamine is considered safe during pregnancy, as it is an essential nutrient.

Breast-feeding

Thiamine is excreted in breast milk, but supplementation is generally considered safe for breastfeeding mothers.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Thiamine hydrochloride injection
• Thiamine hydrochloride oral tablets
• Thiamine hydrochloride oral solution

Indications

• Vitamin deficiency syndromes (e.g., scurvy for vitamin C deficiency, rickets for vitamin D deficiency)
• Support for immune function
• Antioxidant support
• Bone health maintenance
• Vision health
• Energy metabolism support

Dosage

Children: Refer to the BNF for Children for specific vitamin dosing guidelines, which depend on age and nutritional requirements.

Adults: Refer to specific vitamin guidelines as dosage varies significantly depending on the type of vitamin and individual needs.

Mechanism of action

Vitamins function primarily as coenzymes or precursors for coenzymes in enzymatic reactions. For instance, B vitamins are involved in energy metabolism, while vitamins A, C, D, E, and K support various physiological functions including vision, antioxidant activity, calcium regulation, and blood clotting. Each vitamin has a unique mechanism of action based on its structure and role in the body.

Pharmacodynamics

Vitamins exert their effects at the cellular level, influencing metabolic pathways, gene expression, and immune responses. For example, vitamin D regulates calcium and phosphate homeostasis, while vitamin A is crucial for vision and immune function. Deficiencies in vitamins can lead to a range of disorders, highlighting their importance in maintaining health.

Pharmacokinetics

The pharmacokinetics of vitamins vary widely. Fat-soluble vitamins (A, D, E, and K) are stored in liver and adipose tissues and can be released into circulation as needed. Water-soluble vitamins (B-complex and C) are not stored and must be consumed regularly, with excess amounts excreted in urine. Absorption rates, half-lives, and distribution can also differ based on the specific vitamin and individual metabolic factors.

Interactions

• tretinoin+vitamin: Severe (increases risk of vitamin toxicity)
• retinoids+vitamin: Severe (increases risk of vitamin toxicity)
• retinoids+vitamin: Moderate (increases risk of toxicity)
• carbamazepine+vitamin: Unknown (decreases effects)
• cobicistat+vitamin: Unknown (increases exposure)
• vitamin D substances+digoxin: Unknown (increases risk of toxicity)
• idelalisib+vitamin: Unknown (increases exposure)
• clarithromycin+vitamin: Unknown (increases exposure)

Pregnancy

Consult healthcare professional before use. Vitamin supplementation during pregnancy should be carefully managed to avoid hypervitaminosis.

Breast-feeding

Consult healthcare professional before use. Some vitamins can pass into breast milk and may affect the infant.

Storage

Store in a cool, dry place, away from direct sunlight. Ensure it is kept out of reach of children.

Formulations

• {'name': 'Vitamin A', 'form': 'Capsule', 'strength': '10000 IU'}
• {'name': 'Vitamin D', 'form': 'Tablet', 'strength': '1000 IU'}
• {'name': 'Vitamin E', 'form': 'Softgel', 'strength': '400 IU'}

Mechanism of action

Binds to riboflavin hydrogenase, riboflavin kinase, and riboflavin synthase. Riboflavin is the precursor of flavin mononucleotide (FMN, riboflavin monophosphate) and flavin adenine dinucleotide (FAD). The antioxidant activity of riboflavin is principally derived from its role as a precursor of FAD and the role of this cofactor in the production of the antioxidant reduced glutathione. Reduced glutathione is the cofactor of the selenium-containing glutathione peroxidases among other things. The glutathione peroxidases are major antioxidant enzymes. Reduced glutathione is generated by the FAD-containing enzyme glutathione reductase. Riboflavin is converted to 2 coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are necessary for normal tissue respiration. Riboflavin is also required for activation of pyridoxine, conversion of tryptophan to niacin, and may be involved in maintaining erythrocyte integrity. Riboflavin functions as the coenzyme for flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which primarily influence hydrogen transport in oxidative enzyme systems (eg, cytochrome C reductase, succinic dehydrogenase, xanthine oxidase). Two active forms of riboflavin exist ... coenzyme flavin mononucleotide (FMN) and coenzyme flavin adenine dinucleotide (FAD). They are formed by reaction of riboflavin with 1 and 2 molecules of ATP as follow: riboflavin + ATP = riboflavin-P (FMN) + ADP; FMN + ATP = riboflavin-ADP (FAD) + PP. Riboflavin is a water-soluble, yellow, fluorescent compound. The primary form of the vitamin is as an integral component of the coenzymes flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD). It is in these bound coenzyme forms that riboflavin functions as a catalyst for redox reactions in numerous metabolic pathways and in energy production. ... The redox reactions in which flavocoenzymes participate include flavoprotein-catalyzed dehydrogenations that are both pyridine nucleotide (niacin) dependent and independent, reactions with sulfur-containing compounds, hydroxylations, oxidative decarboxylations (involving thiamin as its pyrophosphate), dioxygenations, and reduction of oxygen to hydrogen peroxide. There are obligatory roles of flavocoenzymes in the formation of some vitamins and their coenzymes. For example, the biosynthesis of two niacin-containing coenzymes from tryptophan occurs via FAD-dependent kynurenine hydroxylase, an FMN-dependent oxidase catalyzes the conversion of the 5'-phosphates of vitamin B6 to coenzymic pyridoxal 5'-phosphate, and an FAD-dependent dehydrogenase reduces 5,10-methylene-tetrahydrofolate to the 5'-methyl product that interfaces with the B12-dependent formation of methionine from homocysteine and thus with sulfur amino acid metabolism. For more Mechanism of Action (Complete) data for Riboflavin (7 total), please visit the HSDB record page.

Pharmacodynamics

Riboflavin or vitamin B2 is an easily absorbed, water-soluble micronutrient with a key role in maintaining human health. Like the other B vitamins, it supports energy production by aiding in the metabolising of fats, carbohydrates, and proteins. Vitamin B2 is also required for red blood cell formation and respiration, antibody production, and for regulating human growth and reproduction. It is essential for healthy skin, nails, hair growth and general good health, including regulating thyroid activity. Riboflavin also helps in the prevention or treatment of many types of eye disorders, including some cases of cataracts.

Mechanism of action

It is thought that the mechanism of action of thiamine on endothelial cells is related to a reduction in intracellular protein glycation by redirecting the glycolytic flux. Thiamine is mainly the transport form of the vitamin, while the active forms are phosphorylated thiamine derivatives. Natural derivatives of thiamine phosphate, such as thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and thiamine triphosphate (AThTP), that act as coenzymes in addition to their each unique biological functions. Metabolic control analysis predicts that stimulators of transketolase enzyme synthesis such as thiamin (vitamin B-1) support a high rate of nucleic acid ribose synthesis necessary for tumor cell survival, chemotherapy resistance, and proliferation. Metabolic control analysis also predicts that transketolase inhibitor drugs will have the opposite effect on tumor cells. This may have important implications in the nutrition and future treatment of patients with cancer.

Pharmacodynamics

Thiamine is a vitamin with antioxidant, erythropoietic, cognition-and mood-modulatory, antiatherosclerotic, putative ergogenic, and detoxification activities. Thiamine has been found to protect against lead-induced lipid peroxidation in rat liver and kidney. Thiamine deficiency results in selective neuronal death in animal models. The neuronal death is associated with increased free radical production, suggesting that oxidative stress may play an important early role in brain damage associated with thiamine deficiency. Thiamine plays a key role in intracellular glucose metabolism and it is thought that thiamine inhibits the effect of glucose and insulin on arterial smooth muscle cell proliferation. Inhibition of endothelial cell proliferation may also promote atherosclerosis. Endothelial cells in culture have been found to have a decreased proliferative rate and delayed migration in response to hyperglycemic conditions. Thiamine has been shown to inhibit this effect of glucose on endothelial cells.

Mechanism of action

Plant growth regulator with systemic properties. Penetrates into the plant tissues, and is decomposed to ethylene, which affects the growth processes. Studies have established the variety of target sites in pests and nontarget organisms at which the metabolically activated organophosphorus pesticides act. The high potency and specificity of the organophosphorus pesticides have made these cmpd useful chemical probes to further the knowledge of their mode of action and their metabolism. Many organophosphorus pesticides have been classified as phosphorylating agents. Some enzymes inhibited by organophosphorus cmpd have included acetylcholinesterase, kynurenine formamidase, neuropathy-target esterase, carboxyesterases, and other unknown esterases. Bioactive phosphorylating agents have been designed that are sufficiently stable to reach the organism, yet are reactive at the target site. The majority of organophosphorus bioactivations have been initiated by oxidation at sulfur or nitrogen connected to phosphorus, but some bioactivations involve oxidation at carbon or heteroatom centers distant from phosphorus. The phosphorus center is not the toxic site of some organophosphorus cmpd. The toxic effects of phosphinyliminodithiolanes, phosphorothionates, and ethephon are mediated through other reactive moieties. Butyrylcholinesterase (BChE) is inhibited by the plant growth regulator (2-chloroethyl)phosphonic acid (ethephon) as observed 25 years ago both in vitro and in vivo in rats and mice and more recently in subchronic studies at low doses with human subjects. The proposed mechanism is phosphorylation of the BChE active site at S198 by ethephon dianion. The present study tests this hypothesis directly using [(33)P]ethephon and recombinant BChE (rBChE) with single amino acid substitutions and further evaluates if BChE is the most sensitive esterase target in vitro and with mice in vivo. [(33)P]Ethephon labels purified rBChE but not enzymatically inactive diethylphosphoryl-rBChE (derivatized at S198 by preincubation with chlorpyrifos oxon) or several other esterases and proteins. Amino acid substitutions that greatly reduce rBChE sensitivity to ethephon are G117H and G117K in the oxyanion hole (which may interfere with hydrogen bonding between glycine-N-H and ethephon dianion) and A328F, A328W, and A328Y (perhaps by impeding access to the active site gorge). Other substitutions that do not affect sensitivity are D70N, D70K, D70G, and E197Q which are not directly involved in the catalytic triad. The effect of pH and buffer composition on inhibition supports the hypothesis that ethephon dianion is the actual phosphorylating agent without activation by divalent cations. Human plasma BChE in vitro and mouse plasma BChE in vitro and in vivo are more sensitive to ethephon than any other esterases detected by butyrylthiocholine or 1-naphthyl acetate hydrolysis in native-PAGE. All mouse liver esterases observed are less sensitive than plasma BChE to ethephon in vitro and in vivo. More than a dozen other esterases examined are 10-100-fold less sensitive than BChE to ethephon. Thus, BChE inhibition continues to be the most sensitive marker of ethephon exposure.