In 1940, the world of pharmacology was revolutionized by the appearance of the first edition of this now-classic text. Edited by Lou Goodman and Al Gilman, it was a joy to read and a beacon in the darkness for teachers, students, and practitioners. (I can recall physicians saying they kept it on their bedside table for their nightly reading and pleasure.) The new edition remains a competently written and authoritative book, although it is now put together by 58 people instead of two, with the inevitable problems posed by such a division of labor. (One may envy the editors and the publishers the income from this best seller, but not the task of nagging recalcitrant authors with no respect for deadlines.) One may question, however, as in recent editions, the wisdom of combining a textbook for students and a reference for physicians. Those of us who teach second-year medical students

Goodman & Gilman's The Pharmacological Basis of Therapeutics

Parkinson's disease: Mechanisms and models

The glutathione S-transferases (GST) represent a major group of detoxification enzymes. All eukaryotic species possess multiple cytosolic and membrane-bound GST isoenzymes, each of which displays distinct catalytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designated class alpha, mu, pi, sigma, and theta GST), whereas the membrane-bound enzymes, microsomal GST and leukotriene C, synthetase, are encoded by single genes and both have arisen separately from the soluble GST. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress.A description of the mechanisms of transcriptional and posttranscriptional regulat...

The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance.

https://cyberleninka.org/article/n/148766.pdf

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation

The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Trimethylaminuria (fish-odour syndrome): an inborn error of oxidative metabolism.

1. The excretion and metabolism of [2-(14)C]cimetidine (500 mg orally) was studied in five male volunteers. 2. Over 70% of the 14C was excreted in the urine after 24 h by all individuals with 5% in the faeces; 97% being recovered in total after three days. 3. Unchanged cimetidine was the largest urinary component (63%), followed by a polar conjugate tentatively identified as cimetidine N'-glucuronide (24%). Smaller amounts of the oxidized metabolites, cimetidine sulphoxide and 5-hydroxymethylcimetidine, together with the hydrolysis products, cimetidine guanylurea and cimetidine guanidine, were also observed. 4. Cimetidine and its sulphoxide were identified in faecal samples. Anaerobic incubations of cimetidine or cimetidine sulphoxide with faecal homogenates showed that reduction was the predominant reaction under these conditions. 5. Studies in one individual over a wide dose range (0.5 mg to 1.5 g orally) showed little variation in excretory profile or metabolic spectrum.

The metabolism of [14C]cimetidine in man

Polymorphic CYP2D6 is the enzyme that activates the opioid analgesic tramadol by O-demethylation to its active metabolite O-demethyltramadol (M1). Our objective was to determine the opioid effects measured by pupillary response to tramadol of CYP2D6 genotyped volunteers in relation to the disposition of tramadol and M1 in plasma. Tramadol displayed phenotypic pharmacokinetics and it was possible to identify poor metabolizers (PM) with >99% confidence from the metabolic ratio (MR) in a single blood sample taken between 2.5 and 24 h post-dose. Homozygous extensive metabolizers (EM) differed from PM subjects by an almost threefold greater (P=0.0014) maximal pupillary constriction (Emax). Significant correlations between the AUC and Cmax values of M1 versus pupillary constriction were found. The corresponding correlations of pharmacokinetic parameters for tramadol itself were weaker and negative. The strongest correlations were for the single-point metabolic ratios at all sampling intervals versus the effects, with rs ranging from 0.85 to 0.89 (p<0.01). It is concluded that the concept of dual opioid/non-opioid action of the drug, though considerably stronger in EMs, is valid for both EM and PM subjects. This is the theoretical basis for the frequent use and satisfactory efficacy of tramadol in clinical practice when given to genetically non-selected population.

/pdf/miotic-action-of-tramadol-is-determined-by-cyp2d6-genotype-2mdttxnvu9.pdf

Miotic action of tramadol is determined by CYP2D6 genotype.

The cytochrome P450 CYP2D6 is a polymorphic enzyme, for which 5%-10% of Caucasians (poor metabolizers) lack activity. The majority of mutations giving rise to the deficiency have now been identified but some individuals show anomalous phenotype-genotype relationships when screened for the common mutant alleles. We have sequenced all nine exons and intron-exon boundaries in a subject who was phenotypically a poor metabolizer but genotypically heterozygous when screened for the common alleles. A single base-pair deletion (T1795) was detected in exon 3 and a base substitution (G2064A) resulting in an amino acid substitution (G212E) in exon 4. The deletion results in premature termination of translation and a truncated protein. In a group of 50 white Americans, the allele frequency for the new mutant allele was 0.01. The new allele explains some cases of anomalous genotype/phenotype relationships for CYP2D6.

An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution.

Eleven subjects of previously determined debrisoquine oxidation phenotype status (extensive metabolizer [EM], n = 5; poor metabolizer [PM], n = 6) were studied for their ability to perform the aromatic 4-hydroxylation of phenytoin. The PM subjects studied were found to be slower metabolizer s of phenytoin than EM subjects in terms of the metabolite formation rate constant (kfHPPH: EM, 0.030 ± 0.007 hr−1; PM, 0.016 ± 0.003 hr−1 2p < 0.001) and cumulative excretion of 4-hydroxyphenytoin (48 hr after dosing: EM, 52.8 ± 10.7%; PM, 36.9 ± 7.0%, 2p < 0.01). It is concluded that the metabolic oxidation of phenytoin is influenced by the same DH and DL alleles, acting at the same locus, that regulate the hydroxylation of debrisoquine and that impaired metabolism of phenytoin may be expected to occur in about 9% of the population, being transmitted as an autosomal-recessive trait. It is suggested that debrisoquine oxidation phenotyping may have predictive value in guiding phenytoin dosage, particularly in those with impaired oxidation.



Clinical Pharmacology and Therapeutics (1981) 29, 493–497; doi:10.1038/clpt.1981.68

Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation.

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