Metabohsm hydroxylation

Ketopregnan-21-oic Acids, the 17(3-Carboxy Androstanes, and the D-Homocorticoids. In the course of studies on the metabohsm of fluocoitolone (103) the formation of the water-soluble carboxyhc acid (105, R = H) was reported. As a free 21-hydroxyl is not necessary for antiinflammatory activity, it was concluded that the esters (105, R = alkyl) of the preceding metabohte would possess antiinflammatory activity on topical administration but would be devoid of systemic activity when hydrolysis to the free acid occurs followed by... 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Dmg metaboHsm may also produce toxic materials. Thus, the aromatic hydroxylation of hydrocarbons such as ben2pyrene produces the highly reactive and carcinogenic 1,2-epoxides. 

In rats, the oxidative and reductive metaboHsm products have been identified as the 4-hydroxylated furan and [(3-cyano-l-oxopropyl)methyleneamino]-2-4-imidazohdinedione, respectively (27,42). In addition, the ease of electron transfer as a mechanism of activity with nitrofurantoin and nitrofurazone has been studied (43). 

Oxidative Reactions. The majority of pesticides, or pesticide products, are susceptible to some form of attack by oxidative enzymes. For more persistent pesticides, oxidation is frequently the primary mode of metaboHsm, although there are important exceptions, eg, DDT. For less persistent pesticides, oxidation may play a relatively minor role, or be the first reaction ia a metaboHc pathway. Oxidation generally results ia degradation of the parent molecule. However, attack by certain oxidative enzymes (phenol oxidases) can result ia the condensation or polymerization of the parent molecules this phenomenon is referred to as oxidative coupling (16). Examples of some important oxidative reactions are ether cleavage, alkyl-hydroxylation, aryl-hydroxylation, AJ-dealkylation, and sulfoxidation. 

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting direcdy with nitrites, and consequently may potentially reduce cancer risk. 

Iron Absorption. A very important effect of ascorbic acid is the enhancement of absorption of nonheme iron from foods. Ascorbic acid also enhances the reduction of ferric iron to ferrous iron. This is important both in increasing iron absorption and in its function in many hydroxylation reactions (140,141). In addition, ascorbic acid is involved in iron metaboHsm. It serves to transfer iron to the Hver and to incorporate it into ferritin. 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Clinical stresses which interfere with vitamin metabohsm, can result in calcium deficiency leading to osteomalacia and osteoporosis (secondary vitamin D deficiency). These stresses include intestinal malabsorption (lack of bile salts) stomach bypass surgery obstmctive jaundice alcoholism Hver or kidney failure decreasing hydroxylation of vitamin to active forms inborn error of metabohsm and use of anticonverdiants that may lead to increased requirement. 

Absorption is complete and bioavailabihty is about 100% at steady state during continuous po dosing. There is extensive hepatic first-pass metabohsm to norlorcainide and hydroxylated metaboUtes. Nodorcainide is equipotent and equieffective to lorcainide in antiarrhythmic activity. 

An important dmg in the regulation of cholesterol metaboHsm is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the Hver to its active, P-hydroxylated form (5). 

The onward metabohsm of succinate, leading to the regeneration of oxaloacetate, is the same sequence of chemical reactions as occurs in the P-oxidation of fatty acids dehydrogenation to form a carbon-carbon double bond, addition of water to form a hydroxyl group, and a hirther dehydrogenation to yield the oxo- group of oxaloacetate. 

Mamiya K, leiri I, Shimamoto J, Yukawa E, Imai J, Ni-nomiya H et al. The effects of genetic polymorphims of CYP2C9 and CYP2C19 on phenytoin metabohsm in Japanese adult patients with epilepsy studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998 29(12) 1317-23. 

The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and A-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabohsm occurs in the intestinal mucosa (mostly A-acetylation) and the hver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces. 

Kinetic parameters of metabolism of fluorinated analogues of propanolol by cytochrome enzyme (recombinant CYP1A2) have been determined. They clearly indicate that the A-dealkylation process was 10-fold lower for the N—CH2CF3 compound with respect to propanolol itself. Hydroxylation of the naphthalene ring process is not observed in the case of propanolol but it becomes the major process with the fluoro analogue (Figure 3.13)." The same decreased metabohsm trend has also been observed with lower pKa values for CYP2D6 cytochrome enzyme." ... 

One of the more important routes for the metabohsm of benzodiazepines involves the introduction of a hydroxyl group at the 3 position in the heterocychc ring. The fact... 

Capsaicin and capsaicinoids undergo Phase I metabolic bioconversion to catechol metabolites via hydroxylation of the vanillyl ring moiety (Lee and Kumar, 1980 Miller et al, 1983). Metabohsm involves oxidative, in addition to non-oxidative, mechanisms. An example of oxidative conversion involves the liver mixed-function oxidase system to convert capsaicin to an electrophilic epoxide, a reactive metabolite (Olajos, 2004). Surh and Lee (1995) have also demonstrated the formation of a phenoxy radical and quinine product the quinine pathway leads to formation of a highly reactive methyl radical (Reilly et al, 2003). The alkyl side chain of capsaicin also undergoes rapid oxidative deamination (Wehmeyer et al, 1990) or hydroxylation (Surh et al, 1995 Reilly et al, 2003) to hydroxycapsaicin as a detoxification pathway. An example of nonoxidative metabolism of capsaicin is hydrolysis of the acid-amide bond to yield vanillylamide and fatty acyl groups (Kawada et al, 1984 Oi et al, 1992). 

Cytochromes P450 (P450) form a large family of heme enzymes that catalyze a diversity of transformations including epoxidation, hydroxylation and heteroatom oxidation. The enzymes are involved in the metabohsm of many... 

---