Enzymic metabolism

It is not presently known what phase I enzymes metabolize methyl parathion, and consequently, whether metabolism differs between children and human adults. There is some suggestive evidence for age-related differences in metabolism of methyl parathion in rats (Benke and Murphy 1975). 

Various factors affect the activities of the enzymes metabolizing xenobiotics. The activities of these enzymes may differ substantially among species. Thus, for example, the possible toxicity or carcinogenicity of xenobiotics cannot be extrapolated freely from one species to another. There are significant differences in enzyme activities among individuals, many of which appear to be due to genetic factors. The activities of some of these enzymes vary according to age and sex. 

Kay, K. (1970) Pesticides and associated health factors in agricultural environments effects on mixed-function oxiding enzyme metabolism, pulmonary surfactant and immunological reactions, in Pesticides Symposia, R. Dichmann (Ed.), Halos Co., Miami, FL. 

Mandagere, A. K., T. N. Thompson, and K. K. Hwang. Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates, J. Med. Chem. 2002, 45, 304-311... 

In the first family, the metal is coordinated by one molecule of the pterin cofactor, while in the second, it is coordinated to two pterin molecules (both in the guanine dinucleotide form, with the two dinucleotides extending from the active site in opposite directions). Some enzymes also contain FejSj clusters (one or more), which do not seem to be directly linked to the Mo centers. The molybdenum hydroxylases invariably possess redox-active sites in addition to the molybdenum center and are found with two basic types of polypeptide architecture. The enzymes metabolizing quinoline-related compounds, and derivatives of nicotinic acid form a separate groups, in which each of the redox active centers are found in separate subunits. Those enzymes possessing flavin subunits are organized as a2jS2A2, with a pair of 2Fe-2S centers in the (3 subunit, the flavin in the (3 subunit, and the molybdenum in the y subunit. 

Mirex has considerable potential for chronic toxicity because it is only partly metabolized, is eliminated very slowly, and is accumulated in the fat, liver, and brain. The most common effects observed in small laboratory mammals fed mirex included weight loss, enlarged livers, altered liver enzyme metabolism, and reproductive failure. Mirex reportedly crossed placental membranes and accumulated in fetal tissues. Among the progeny of mirex-treated mammals, developmental abnormalities included cataracts, heart defects, scoliosis, and cleft palates (NAS 1978 Blus 1995). 

There are also numerous enzymes anchored in membranes of the microsomal cell fraction that participate in the metabolism of steroid hormones. Thus, those of the p450 family, which carry out molecular oxidation, or the sulfatases and sulfotransferases, more or less specific to several hormones (Pasqualini et al. 1995). The affinity of steroid hormones for proteins of the membrane (Kd between 10 and 100 nM) is frequently greater than that which some of these enzymes present for their substrates (Luzardo et al. 2000). Therefore, it is unlikely that a part of the proteins of the membrane that bind steroids is in reality enzymes metabolizing these hormones. 

Phenol is a hydrolyzed metabolite of benzene and is itself further hydrolyzed or conjugated to produce other compounds. Therefore, the toxic effects of phenol exposure may be due to a combination of the parent compound and its metabolites. The major tissues in which metabolism appears to occur are the liver, gut, lung, and kidney (Cassidy and Houston 1984 Powell et al 1974 Quebbemann and Anders 1973 Tremaine et al. 1984). Since phenol, benzene, and their major metabolites all seem to compete for the same P450 and conjugating enzymes, metabolic reactions are presumed to be saturable. 

The MAO enzymes, which come in two types known as MAO-A and MAO-B, perform a scavenger function by metabolizing and thereby eliminating certain molecules from nerve cells. This prevents the accumulation of toxic levels of these substances. In the brain, the MAO-A enzyme metabolizes a variety of substances including norepinephrine and serotonin, and the MAO-B enzyme metabolizes dopamine and several other substances. The effectiveness of MAOIs primarily comes from their ability to inhibit the MAO-A enzyme and thereby boost the availability of norepinephrine and serotonin. 

Drug-drug interactions are often more problematic with carbamazepine than other mood stabilizers. Carbamazepine increases the activity of certain liver enzymes. Because these enzymes metabolize and eliminate medications and other substances introduced to the body, carbamazepine therapy can decrease the blood level and thereby reduce the effectiveness of itself (a phenomenon called autoinduction) and other medications that are metabolized by these enzymes. It is not unusual to find that the dose of carbamazepine must be increased after several weeks, because it has increased its own elimination. Other medications may likewise be less effective. Of particular concern are the oral contraceptives, Depo-Provera, and protease inhibitors used for the treatment of HI V+ patients. Oral contraceptives often require an increase in dose. 

A combination of various properties of antipyrine gives it an advantage over other microsomal enzyme metabolizing drugs. These include high oral availability useful for non-invasive oral administration, lack of plasma protein binding which prevents environmental clearance variability, and fast distribution... 

Determination of the level of cytosolic enzymes such as aspartate transaminase, alanine transaminase, and lactate dehydrogenase is part of standard biochemical liver function tests to measure hepatocellular necrosis [2, 101]. Cytosolic enzymes are not subject to genetic variations inherent in microsomal enzyme production. Liver cytosolic enzymes metabolize several molecules, of which galactose and amino acids are typical examples, used for hepatic function tests. 

Metabolism - Dantrolene is found in measurable amounts in blood and urine. Mean half-life in adults is 9 hours after a 100 mg oral dose and 4 to 8 hours after IV administration. Because it is probably metabolized by hepatic microsomal enzymes, metabolism enhancement by other drugs is possible. 

Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility,... 

Because bupropion is metabolized in the liver, medications that alter hepatic enzyme metabolism, such as carbamazepine or cimetidine, may effect blood concentrations. Bupropion should not be administered in combination with the MAOIs because of risk of hypertensive crisis. Levo-dopa use in conjunction with bupropion has been associated with confusion, hallucinations, and dyskinesia. Although generally well tolerated, there are case reports documenting that the... 

Chi, Y.S. et al., Effects of naturally occurring prenylated flavonoids on enzymes metabolizing arachidonic acid cyclooxygenases and lipoxygenases, Biochem. Pharmacol., 62, 1185, 2001. 

Drug interactions No drug interaction studies have been conducted with Avonex. Other interferons have been found to reduce cytochrome P-450-mediated drug metabolism. Hepatic microsomes isolated from Avonex-treated rhesus monkeys showed no influence on hepatic P-450 enzyme metabolism activity. 

Verapamil, diltiazem, and perhaps nicardipine (but not nifedipine) inhibit hepatic drug-metabolizing enzymes. Metabolism of diltiazem, nifedipine, verapamil, and probably other calcium channel blockers subject to induction and inhibition. 

The cDNA expression systems can be used to address questions such as can human enzymes metabolize a xenobiotic What are the metabolites Can human enzymes activate a protoxin In order to adequately support a negative conclusion it is obvious that the range of cytochrome P450 enzymes examined needs to be as comprehensive as possible. 

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