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The electrons are donated The CYP3A4 isoform accounts for 60% of CYP450 enzymes in the liver and by the cytochrome P450 reductase cheap cialis extra dosage 200mg without a prescription erectile dysfunction doctors fort worth, which con- 70% of cytochrome enzymes in gut wall enterocytes order 40mg cialis extra dosage erectile dysfunction university of maryland. It metabolizes the greatest tains an FAD plus an FMN or Fe-S center to number of drugs in humans. The con- facilitate the transfer of single electrons from comitant ingestion of two CYP3A4 substrates could potentially induce competition NADPH to O2. The P450 enzymes involved in for the binding site, which, in turn, could alter the blood levels of these two agents. For CYP2E1, RH is ethanol The drug with the highest affinity for the enzyme would be preferentially metabo- (CH3CH2OH), and ROH is acetaldehyde lized, whereas the metabolism (and degradation) of the other drug would be (CH3COH). The latter drug’s concentration in the blood would then rise. Moreover, many substances or drugs impair or inhibit the activity of the CYP3A4 enzyme, thereby impairing the body’s ability to metabolize a drug. The lipid-lowering agents known as the statins (HMGCoA reductase inhibitors) require CYP3A4 for degradation. Appropriate drug treatment and dosing takes into account the normal degradative pathway of the drug. However, grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism. Evidence suggests that if a statin is regularly taken with grapefruit juice, its level in the blood may increase as much as 15-fold. This marked increase in plasma concentration could increase the muscle and liver toxicity of the statin in question. The cytochrome P450 isozymes all have certain features in common: 1. They all contain cytochrome P450, oxidize the substrate, and reduce oxygen. They all have a flavin-containing reductase subunit that uses NADPH, and not NADH, as a substrate. They are all found in the smooth endoplasmic reticulum and are referred to as microsomal enzymes (for example, CYP2E1 is also referred to as the microso- mal ethanol oxidizing system, MEOS). They are all bound to the lipid portion of the membrane, probably to phos- phatidylcholine. They are all inducible by the presence of their own best substrate and somewhat less inducible by the substrates for other P450 isozymes. They all generate a reactive free radical compound as an intermediate in the reaction. EXAMPLES OF CYTOCHROME P450 DETOXIFICATION REACTIONS i. Vinyl Chloride The detoxification of vinyl chloride provides an example of effective detoxification by a P450 isozyme (ethanol detoxification was previously discussed in Chapter 25). Vinyl chloride is used in the synthesis of plastics and can cause angiosarcoma in the liver of exposed workers. It is activated in a phase I reaction to a reactive epoxide by 848 SECTION EIGHT / TISSUE METABOLISM Phase I O Phase II H H reaction reactions H C CH2 C Cl ClCH2 C H Cl CYP2E1 H O Vinyl chloride Chloroethylene Chloroacetaldehyde oxide glutathione S-transferase Covalent binding Conjugation with to proteins, DNA; glutathione, cell damage excretion Fig. However, it also can be converted to chloroacetate, conjugated with reduced glutathione, and excreted in a series of phase II reactions (Fig. Aflatoxin B1 Aflatoxin B1 is an example of a compound that is made more toxic by a cytochrome P450 reaction (CYP2A1). Current research suggests that ingested aflatoxin B1 in contaminated food (it is produced by a fungus [Aspergillus flavus] that grows on peanuts that may have been stored in damp conditions) is directly involved in hepa- tocarcinogenesis in humans by introducing a G > T mutation into the p53 gene. Aflatoxin is metabolically activated to its 8,9 epoxide by two different isozymes of cytochrome P450. The epoxide modifies DNA by forming covalent adducts with guanine residues. In addition, the epoxide can combine with lysine residues within proteins and thus is also a hepatotoxin. Acetaminophen Acetaminophen (Tylenol) is an example of a xenobiotic that is metabolized by the liver for safe excretion; however, it can be toxic if ingested in high doses. The pathways for acetaminophen metabolism are shown in Fig.

INSULIN AND GROWTH HORMONE log) (see Chapter 6 cialis extra dosage 40mg cheap erectile dysfunction lisinopril, Fig generic cialis extra dosage 100mg line erectile dysfunction pills thailand. Lispro was genetically engineered so that Recombinant DNA techniques are used to produce proteins that have therapeutic lysine is at position 28 and proline is at posi- properties. One of the first such proteins to be produced was human insulin. Di and inserted into plasmids that were used to transform E. The bacteria injects a Humalog mixture that contains 75% then synthesized the insulin chain, which was purified. A similar process was used lispro protamine suspension (intermediate- to obtain B chains. The A and B chains were then mixed and allowed to fold and acting) and 25% lispro solution (rapid-act- form disulfide bonds, producing active insulin molecules (Fig. The switch of position of the two amino glycosylated, so there was no problem with differences in glycosyltransferase activ- acids leads to a faster-acting insulin ity between E. The lispro is absorbed from the site of injection much more quickly than Human growth hormone has also been produced in E. Before production of recombinant blood glucose levels much more rapidly growth hormone, growth hormone isolated from cadaver pituitary tissue was used, than the other insulin forms. COMPLEX HUMAN PROTEINS promoter Insulin Insulin A chain B chain More complex proteins have been produced in mammalian cell culture using Vector recombinant DNA techniques. The gene for Factor VIII, a protein involved in blood clotting, is defective in individuals with hemophilia. Before genetically engineered Factor VIII became available, a number of hemophiliac patients died of AIDS or AmpR hepatitis that they contracted from transfusions of contaminated blood or from Transform into E. Tissue plasminogen activator (TPA) is a protease in blood that converts plas- minogen to plasmin. Plasmin is a protease that cleaves fibrin (a major component of blood clots), and, thus, TPA administration dissolves blood clots. Recombinant TPA, produced in mammalian cell cultures, is frequently administered during or Vector Bacterial immediately after a heart attack to dissolve the thrombi that occlude coronary arter- chromosome ies and prevent oxygen from reaching the heart muscle. Culture cells Hematopoietic growth factors also have been produced in mammalian cell cul- tures by recombinant DNA techniques. Erythropoietin can be used in certain types Purify insulin of anemias to stimulate the production of red blood cells. Colony-stimulating fac- chains tors (CSFs) and interleukins (ILs) can be used after bone marrow transplants and after chemotherapy to stimulate white blood cell production and decrease the risk of infection. A chain B chain Recombinant -interferon is the first drug known to decrease the frequency and severity of episodes resulting from the effects of demyelination in patients with Refold and oxidize multiple sclerosis. These animals (usually goat or sheep) have been genetically engineered to A chain NH2 COOH Active produce human proteins in the mammary gland and secrete them into milk. The B chain NH2 COOH insulin gene of interest is engineered to contain a promoter that is only active in the Disulfide bond mammary glands under lactating conditions. Amp the gene for ampicillin resist- implanted into a foster mother. The female animal progeny are tested for the pres- R ance. The presence of Amp allows bacterial ence of this transgene, and milk from the positive animals is collected. Large quan- cells that contain the vector to grow in the tities of the protein of interest can then be isolated from the relatively small number presence of ampicillin. Genetic Counseling thetic scheme was developed whereby each individual chain of insulin was expressed, pro- One means of preventing disease is to avoid passing defective genes to offspring. If duced, and purified, and then the two chains individuals are tested for genetic diseases, particularly in families known to carry a were linked together in a test tube.

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In normal gait cheap 60mg cialis extra dosage with amex erectile dysfunction symptoms causes, this rotation around the mechanical axis of the femur allows the feet to stay in the midline and allows the pelvis to turn on top of the femur cheap 200mg cialis extra dosage visa erectile dysfunction statistics worldwide, which are both motions that work to decrease movement of the HAT segment and therefore conserve energy. At initial contact, the normal hip has slight external rotation of ap- proximately 10°, then it slowly internally rotates, reaching a maximum at terminal stance or initial swing phase. If the hip is positioned in internal ro- tation at initial contact, then during stance phase as the knee flexes, there is an obligatory hip adduction and the knee may impact the opposite limb (Case 7. If the internal rotation is present during midstance, such as in a crouched gait pattern, the knees often rub during swing phase of the con- tralateral limb. Internal rotation positioning in terminal swing also causes the knee to cross the midline, a problem that continues into initial swing. Another primary effect of this internal rotation is placing the knee axis out of line with the forward line of motion. This position causes significant alter- ation in mechanical efficiency of the push-off power that the ankles gener- ate. Secondary adaptation to the internal rotation of the hip includes de- creased knee flexion in weight acceptance in swing phase, decreased ankle push-off power burst, and requires the use of more hip power. If the inter- nal rotation is unilateral, the pelvis may rotate posteriorly on the side of the internal hip rotation, then the contralateral hip compensates with external rotation. The amount of internal rotation is assessed by physical examination with children prone and the hips extended (Case 7. There are two problems with the kinematic measure of which clinicians must always be aware. First, the measure is very dependent on defining the axis of the knee joint by the person placing the marker. An error of 5° to 10° in defining the knee joint axis is to be expected. The sec- ond major issue is all clinical gait software programs currently use rotation as the last Euler angle to derotate. This means that often the measured de- gree of rotation is less than clinicians perceive, probably because they are mentally derotating the hip first. This is not an error in the kinematics or the clinicians’ assessments but is related only to the method of expressing the po- sition. Clinically, the hip rotation may be more significant than the kinematic measure suggests. The principal cause of the increased internal rotation is increased femoral anteversion. A secondary cause may be a contracture of the inter- nal rotators. A third cause may be motor control problems as mentioned with increased scissoring, which are often seen in marginal ambulators. For children who previously had surgery on the hip and in whom there is a ques- tion as to the specific cause of the internal rotation, measurement of the femoral anteversion with ultrasound or CT scan should be considered. Children in middle childhood or older who are functional ambulators tend to do poorly with internal rotation that is greater than 10° during terminal stance phase. From middle childhood on, there is little apparent sponta- neous correction of the internal rotation. Children who are very functional ambulators and have any internal rotation during stance phase are easily cosmetically observed as having internal rotation. Some children with 0° to 15° of internal rotation of the hip in stance phase seem to have very few measurable mechanical problems; however, parents often notice that they trip more frequently, which may be due to decreased knee flexion to avoid Figure 7. Crossing over of the knees is knees crossing over the midline. These increased problems that require so- often called scissoring gait. However, it is phisticated motor control probably cause children with CP to be more better to use the term scissoring gait only when it is caused by true hip hyperadduction. Also, during running when there is increased knee flexion, a heel Most of the time, crossing over of the knees whip will appear if children have persistent internal rotation. This heel is due to internal rotation of the hips, often whip clearly adds to children’s poor coordination during running. Treat- secondary to increased femoral anteversion ment of increased internal rotation is a derotation femoral osteotomy, and not caused by primary increased hip which will improve the foot progression angle.

D2 receptors are expressed by medium spiny neurons containing enkephalin that project to the external segment of the globus pallidus (28) order cialis extra dosage 100mg on line zinc causes erectile dysfunction. The globus pallidus is a major efferent projection system of the striatum that has high densities of D2 receptors (29) purchase 200mg cialis extra dosage fast delivery erectile dysfunction drugs malaysia. However, neurons expressing D2 receptor mRNA are lower in the globus pallidus than in the caudate and putamen, suggesting that most of the D2 protein is located on projections extrinsic to this structure. D2 receptor mRNA is co-localized with enkephalin expression cells in many brain areas, including the periaquaductal grey, suggesting a role for these sites in the modulation of analgesia. The D3 dopamine receptor is highly expressed in limbic brain and has low expression in motor divisions of the striatum (6,30). In vitro receptor autoradiography demonstrates that D3 receptors in the human brain have a distinct localization pattern that is less dense than either D1 or D2 binding sites (Fig. The highest densities of D3 receptors are seen over subcortical limbic brain regions. Low levels of D3 binding sites are seen over the ventromedial (limbic) sectors of the striatum. The highest levels of D3 message expression are found within the telencephalic areas receiving mesocortical dopaminergic inputs, including the islands of Calleja, bed nucleus of the stria terminalis, hippocampus, and hypothalamus. In the cerebellum, Purkinje cells lobules IX and X express abundant D3 mRNA, whereas binding sites are only found in the molecular layer (30,31). Since no known dopaminergic projections are known to exist in this area, it has been suggested that the D3 receptor may mediate the nonsynaptic (paracrine) actions of dopamine (31). D4 receptor message is localized to dopamine cell body fields of the substantia nigra and VTA. This pattern suggests that the D4 receptor protein may function as a presynaptic autoreceptor in dendrites and/or presynaptic terminals (32). The highest areas of D4 expression are found in the frontal cortex, amygdala, and brainstem areas. The very low levels of D4 receptor message in the terminal fields of the striatum are in keeping with the lack of extrapyramidal side effects observed following treatment with putative D4 selective atypical neuroleptics. FIGURE 1 Autoradiographic localization of the distribution of D1, D2, and D3 receptors in representative coronal half-hemisphere sections of the human brain. Brain autoradiograms are shown in pseudocolor codes corresponding to a rainbow scale (red ¼ high densities; green ¼ intermediate densities; purple ¼ low densities) for a control subject (male, age 72 yrs) and a patient with Parkinson’s disease (male, age 67 yrs). The dopamine transporter was labeled with [3H]WIN 35, 428 (panels A and E) and shows the severity of the loss of dopamine terminals in end- stage Parkinson’s disease. Panels B and F illustrate the distribution of D1 3 receptors with 1 nM [ H]SCH 23390 in the presence of 10 nM mianserin to occlude labeling of the 5-HT2 receptor. Panels C and G show the distribution of D2 receptors labeled with 2 nM [3H] raclopride. Panels D and H illustrate the distribution of D3 receptors labeled with [3H]7OH DPAT. Panels C and F show the distribution of D3 receptors labeled with [3H]7OH-DPAT (for method see Ref. Cd, caudate; Gp, globus pallidus; Pt, putamen; Th, thalamus. Previous studies have suggested that D1-like and D2-like receptors may be colocalized in a subpopulation of the same neostriatal cells (33). This hypothesis has been questioned by recent data from Gerfen and coworkers (34), which demonstrated that the interactions may occur at an intercellular level as opposed to an intracellular second messenger integration. This latter hypothesis suggests that the D1-like and D2-like receptor proteins are on distinct populations of neurons with extensive axon collateral systems subserving the integration across neural subfields. However, there is considerable evidence from anatomical and electrophysiological studies that direct cointegration may occur at the single cell level (32,33). This anatomical arrangement would afford D1-mediated cooperative/synergistic control of D2-mediated motor activity and other psychomotor behaviors. Most studies have demonstrated opposing roles of D1 and D2 receptor– mediated actions in the striatum resulting from the stimulation and inhibition of adenylyl cyclase, respectively (35). While more studies are needed to clarify the precise nature and extent of these functional interactions on cyclic adenosine monophosphate (cAMP) second messenger systems, species-specific differences may limit the extrapolation of rodent studies to monkeys and humans (36). Isolated activation of D1 and D2 dopamine receptors produces short- term effects on striatal neurons, whereas the combined stimulation of dopamine and glutamate receptors produces long-lasting modification in synaptic excitability (37). Dopamine terminals arising from the substantia nigra constitute, along with corticostriatal afferents containing glutamate, the majority of axon terminals in the striatum.

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