Alkaline phosphatase distribution

When one takes into consideration the physiological factors which can operate to modify enzyme proteins, one must also include as a fundamental basis of departure the genetic constitution of the individual. At present the traits are associated with ABO blood groups and secretor status. But who knows when the genetic factor may directly explain the individual serum alkaline phosphatase distribution in terms of specific enzymes ... 

Ireland, M. 1986. Effects of wound healing on zinc distribution and alkaline phosphatase activity of Helix aspersa (gastropoda pulmonata). Jour. Mollus. Stud. 52 169-173. 

Phosphates of pharmaceutical interest are often monoesters (Sect. 9.3), and the enzymes that are able to hydrolyze them include alkaline and acid phosphatases. Alkaline phosphatase (alkaline phosphomonoesterase, EC 3.1.3.1) is a nonspecific esterase of phosphoric monoesters with an optimal pH for catalysis of ca. 8 [140], In the presence of a phosphate acceptor such as 2-aminoethanol, the enzyme also catalyzes a transphosphorylation reaction involving transfer of the phosphoryl group to the alcohol. Alkaline phosphatase is bound extracellularly to membranes and is widely distributed, in particular in the pancreas, liver, bile, placenta, and osteoplasts. Its specific functions in mammals remain poorly understood, but it seems to play an important role in modulation by osteoplasts of bone mineralization. 

Nakanishi, T., Tagata, Y. 1972. The distribution and some properties of esterase, alkaline phosphatase and acid phosphatase in cow s milk. Jap. J. Dairy Sci. 21, A-207-215. 

After intravenous administration of etoposide 150 mg/ m, the peak plasma concentration averages 20 micro-grams/ml and the half-life 7.1 hours. Drug clearance and distribution volume are about 16 ml/minute/m and 17 1/ m (6,7,74). With respect to plasma concentrations of etoposide, intravenous etoposide phosphate is equivalent to intravenous etoposide with conventional or intensified dose schedules (75-79). After intravenous administration, the prodrug etoposide phosphate undergoes rapid hydrolysis catalysed by alkaline phosphatase this conversion is linear even at high intravenous doses of 1200 mg/m infused over 2 hours on days 1 and 2. 

There are five enzymes that are commonly used in diagnosis of liver disease Aspartate aminotransferase (AST EC 2.6.1.1), alanine aminotransferase (ALT EC 2.6.1.2), alkaline phosphatase (ALP 3.1.3.1), and y-glutamyl transferase (GGT EC 2.3.2.2), are commonly used to detect liver injury, and lactate dehydrogenase (LD EC 1.1.1.27) is occasionaEy used. ALT and GGT are present in several tissues, but plasma activities primarily reflect liver injury. AST is found in liver, muscle (cardiac and skeletal), and to a liipited extent iti fed cells. LD has wide tissue distribution, and is thus relatively nonspecific. ALP is found in a number of tissues, but in normal individuals primarEy reflects bone and liver sources. Thus based on tissue distribution, ALT and GGT would seem to be the most specific markers for liver injury. 

Proximal tubule cells in culture should have retained functional attributes such as (1) polar architecture and junctional assembly of epithelia and correct membrane distribution of enzymes and transport systems (2) vectorial transport of solutes and water, manifested by the formation of domes when cultured on solid supports [81] and the generation of transepithelial electrophysiological properties [82, 83] due to the expression of proximal tubule specific claudins 2- and 10 [84, 85] (3) cellular uptake of xenobiotics from either the apical or basolateral side, as observed in vivo and (4) expression of nephron segment-specific characteristics, i.e., distinct expression of differentiation markers, metabolic and transport properties, and hormone responsiveness. Such markers include the expression of the brush border enzymes alkaline phosphatase, leucine aminopeptidase, and y-glutamyl transferase [4, 86], In addition, proximal tubule cells should possess Na+,K+-ATPase activities, Na+-dependent glucose, and p-aminohippurate transport. Proximal tubule cells increase cAMP levels in response to parathyroid... 

Other studies have reported raised urinary levels of alkaline phosphatase in a wide variety of renal disease (A2, A14, R22, W4). The patterns of distribution of alkaline phosphatase isozymes in the urines of patients having higher blood levels of this enzyme closely resemble those in the circulation. Urine enzyme may also originate from the prostate (S25). 

K20. Komer, N. H., Distribution of alkaline phosphatase in serum protein fractions. J. Clin. Pathol. 16, 195-199 (1962). 

Often there is no good clinical test available to determine the exact type of hepatic lesion, short of liver biopsy. There are certain patterns of enzyme elevation that have been identified and can be helpful (Table 38-3). ° The specificity of any serum enzyme depends on the distribution of that enzyme in the body. Alkaline phosphatase is found in the bile duct epithelium, bone, and intestinal and kidney cells. 5-Nucleotidase is more specific for hepatic disease than alkaline phosphatase, because most of the body s store of 5 -nucleotidase is in the liver. Glutamate dehydrogenase is a good indicator of centrolobular necrosis because it is found primarily in centrolobular mitochondria. Most hepatic cells have extremely high concentrations of transaminases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are commonly measured. Because of their high concentrations and easy liberation from the hepato-cyte cytoplasm, AST and ALT are very sensitive indicators of necrotic lesions within the liver. After an acute hepatic lesion is established, it may take weeks for these concentrations to return to normal. ... 

Summary of the gene nomenclature, accession numbers, common names, tissue distribution, and function, if known, for the human and mouse alkaline phosphatase isozymes... 

Serum alkaline phosphatase activities of apparently healthy individuals are not evenly distributed about a mean (Fig. 1) but are skewed toward the higher values (ElO, G4, K13, R23). The biological reason for this skewness is not known. Posen (P25) suggested that it may be related to the laws governing the turnover rate of circulating proteins. 

In spite of the skewed distribution of serum alkaline phosphatase values, many authors continue to speak in terms of means and 2 standard deviations even though such cut-off points do not identify the central 95% of observed values. Elveback et al. (ElO) therefore suggested that the upper and lower reference limits be set at 2 and 97y centiles above and below the median value. This is standard practice in expressing other biological values, such as the height of growing children. 

Fig. 1. The distribution of serum alkaline phosphatase values in 208 normal females and 178 normal males examined during the Busselton Survey (B37). Note the non-Caussian distribution and the higher values of males. Data by courtesy of Dr. D. Curnow.

Gardner, M. D., and Scott, R., Frequency distribution and reference values of plasma alkaline phosphatase (EC 3.1.3.1) activity in the adult population of a Scottish new town. J. Clin. Pathol. 31, 1202-1206 (1978). 

K13. Keating, F. R., Jones, J. D., Elveback, L. R., and Randall, R. V., The relation of age and sex to distribution of values in healthy adults of serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, total protein, albumin and blood urea. /. Lab. Clin. Med. 73, 825-834 (1969). 

In practice, using a normal chemistry panel and complete blood count it is not unusual to have 30 potential covariates, everything from sodium ion concentration to alkaline phosphatase activity. Early in PopPK analyses it was not unusual to screen every single covariate for their impact on the model. But a model might end up having a volume of distribution as a function of chloride ion concentration or clearance that is a function of glucose concentration. Physiologically, these covariates are nonsensical. Ideally at the end of model... 

---