Tissue distribution of drug-metabolizing enzymes in humans

Pacifici, Gian Maria; Franchi, M; Bencini, Chiara; Repetti, F; Lascio, Nicole Di; Muraro, G. B.

doi:10.3109/00498258809041723

Cited by 139 publications

(80 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These transferases exhibit distinct but overlapping substrate specificity and are known to catalyze the glucuronidation of a variety of phenols, arylamines, steroids, and bilirubin. Enzymatic activity is highest in the liver, followed by kidney and intestinal mucosa (42). We have shown that human liver microsomes can catalyze the N-glucuronidation of several N-hydroxyarylamines, including those derived from ABP and 2-naphthylamine (43), and from IQ, MeIQx, PhIP, and Glu-P-1 (44).…”

Section: Udp-glucuronosyltransferasesmentioning

confidence: 99%

“…Phenol sulfotransferases, which catalyze the sulfate conjugation of catechol and phenolic drugs and other xenobiotics, have been studied in several human tissues, including the liver, small intestine, cerebral cortex, kidney, and blood platelets (42,51). Two forms of sulfotransferase have been characterized: a thermolabile (TL) form that catalyzes the sulfation of dopamine and other phenolic monoamines and is relatively resistant to inhibition by 2,6-dichloro-4-nitrophenol; and a thermostable (TS) form that catalyzes the sulfation of a variety of phenols, such as p-nitrophenol, and is highly sensitive to 2,6-dichloro-4-nitrophenol inhibition.…”

Section: Sulfotransferasesmentioning

confidence: 99%

See 1 more Smart Citation

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Kadlubar¹,

Butler²,

Kaderlik³

et al. 1992

Environmental Health Perspectives

View full text Add to dashboard Cite

The metabolic pathways associated with carcinogenic aromatic amines in humans provide an excellent example of polymorphisms that appear to be relevant to human carcinogenesis. In this regard, the N-acetylation of arylamines and the O-acetylation of their N-hydroxy metabolites are catalyzed preferentially by a genetically polymorphic acetyltransferase, high activity of which has been correlated with decreased risk for urinary bladder cancer and increased susceptibility to colorectal cancer. Cytochrome P450IA2, the principal liver enzyme involved in aromatic amine N-oxidation, exhibits a wide interindividual variation that appears trimodal in several populations and is clearly inducible by cigarette smoking and probably other host factors as well. UDP-Glucuronosyltransferases, which catalyze the N-glucuronidation of N-hydroxyarylamines and are likely to be responsible for their transport to the colon, show widely varied but unimodal distributions in humans. In contrast, human liver sulfotransferase activity forN-hydroxyarylamines, which would be expected to decrease their transport through the circulation, is catalyzed by a polymorphic enzyme(s) that is expressed at higher levels in blacks, as compared to whites, and could contribute to their relatively lower incidence of urinary bladder cancer. Peroxidative activation of aromatic amines can also occur, especially from prostaglandin H synthase in the urinary bladder and myeloperoxidase in the lungs of cigarette smokers, and both show considerable individual variability, apparently due to the extent of tissue inflammation. In a pilot study, we have examined two of these polymorphisms, acetyltransferase and cytochrome P450IA2, in colorectal cancer/ polyp cases (n = 38) and controls (n = 100) and found that individuals who are both rapid acetylators and rapid N-oxidizers are indeed more prevalent (p < 0.008) among cases (37%) than among controls (16%).

show abstract

Section: Udp-glucuronosyltransferasesmentioning

confidence: 99%

Section: Sulfotransferasesmentioning

confidence: 99%

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Kadlubar¹,

Butler²,

Kaderlik³

et al. 1992

Environmental Health Perspectives

View full text Add to dashboard Cite

show abstract

“…Family 2 enzymes include UGT2A1, 2B4, 2B7, 2B10, 2B11, 2B15 and 2B17, encoded by separate genes, mapped on chromosome 4 [14]. Most human UGT isoforms are expressed in the liver, but high UGT expression levels have also been reported extrahepatically, indicating that other organs also play a major role in glucuronidation [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

Verlaan

Morsche

Pap³

et al. 2004

Pharmacogenetics

View full text Add to dashboard Cite

aObjectives Chronic pancreatitis (CP) is associated with alcohol abuse, smoking and other dietary or environmental factors. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes responsible for glucuronidation of various exogenous and endogenous compounds. Genetic variations, resulting in variable rates of glucuronidation, are of toxicological and physiological importance and are frequently associated with diseases. Recently, a genetic polymorphism in UGT1A7 was possibly associated with an increased risk for CP. We investigated whether polymorphisms in the genes for UGT1A1, UGT1A6 and UGT1A8 modified the risk for CP.Methods DNA samples were obtained from 258 adult CP patients with alcoholic (n 153), hereditary (n 25) or idiopathic (n 80) origin. DNA from 140 healthy controls was analyzed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in UGTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects.Results The distribution of the various alleles of UGT1A1, UGT1A6 and UGT1A8 did not differ between CP patients and healthy controls.Conclusion These data suggest that genetic polymorphisms in UGT1A1, UGT1A6 and in UGT1A8 do not predispose to the development of CP in Caucasians.

show abstract

“…In addition to nonenzymatic conjugation with GSH, glutathione S-transferase (GST) isoforms, which are expressed ubiquitously throughout the body (Pacifici et al, 1988;de Waziers et al, 1990;Awasthi et al, 1994;Rowe et al, 1997), accelerate GSH conjugation by lowering the pKa of the sulfhydryl group of GSH from 9.0 to 6.2-6.7 and increasing the cytosolic concentration of deprotonated GSH (Armstrong, 1997;Fabrini et al, 2011). Therefore, both nonenzymatic and GST-dependent GSH conjugation of the acrylamide moiety in extrahepatic organs as well as in the liver is likely to play a significant role in the pharmacokinetics (PK) of TCI compounds.…”

Section: Introductionmentioning

confidence: 99%

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

Shibata

Chiba

2014

Drug Metab Dispos

View full text Add to dashboard Cite

Despite the fact that much progress has been made recently in the development of targeted covalent inhibitors (TCIs), their pharmacokinetics (PK) have not been well characterized in the light of extrahepatic clearance (CL extH ) by glutathione (GSH)/glutathione S-transferase (GST)-dependent conjugation attributable to the unique electrophilic structure (e.g., acrylamide moiety) of TCI compounds. In the present study, CL extH values were examined in rat, dog, and monkey to predict the contribution of CL extH to the PK of the TCIs afatinib, ibrutinib, and neratinib in humans. Afatinib and neratinib both underwent extensive conjugation with GSH in buffer and cytosol fractions of liver and kidney, whereas ibrutinib showed much lower reactivity/susceptibility to GSH/GST-dependent conjugation. The CL extH in each species was calculated from the difference between observed total body clearance and predicted hepatic clearance (CL H ) in cryopreserved hepatocytes suspended in 100% serum of the corresponding species. The power-based simple allometry relating the CL extH for the unbound compound to animal body weight was applicable across species for afatinib and neratinib (R 2 ‡ 0.9) but not for ibrutinib (R 2 = 0.04). The predicted AUC after oral administration of afatinib and neratinib agreed reasonably closely with reported values in phase I dose-escalation studies. Comparisons of CL extH and CL H predicted that CL extH largely determined the PK of afatinib (>90% as a proportion of total body clearance) and neratinib (∼34%) in humans. The present method can serve as one of the tools for the optimization of PK in humans at the discovery stage for the development of TCI candidates.

show abstract

Tissue distribution of drug-metabolizing enzymes in humans

Cited by 139 publications

References 21 publications

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

Contact Info

Product

Resources

About