Recent advances in hepatic vitamin k metabolism and function

Suttie, John W.

doi:10.1002/hep.1840070226

Cited by 61 publications

(46 citation statements)

References 126 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(2). It has been hypothesized that the cleaved NMTT is responsible for the inhibition of vitamin K metabolism and the subsequent development of antibiotic-associated hypoprothrombinemia (9,11,12,15). In an in vitro model, NMTT has been shown to directly inhibit vitamin K-dependent carboxylase (8,9,14).…”

Section: Resultsmentioning

confidence: 99%

“…Both patient risk factors and the antimicrobial agent are determinants of the prevalence of this event (3, 12, 13). Malnourished or debilitated patients receiving an antibiotic containing the N-methylthiotetrazole (NMTT) side chain appear to be at greatest risk (3,10,12,13).Several theories have been evoked to explain the mechanism of cephalosporins containing the NMTT (cefamandole, cefmenoxime, cefoperazone, cefotetan, and moxalactam) or the N-methylthiadiazole (NMTD) (cefazolin) side chain in potentiating the development of hypoprothrombinemia (9)(10)(11)(12)15 NMTT production was greater for moxalactam than for cefotetan (18). However, comparative information in vivo is lacking.…”

mentioning

confidence: 99%

“…Several theories have been evoked to explain the mechanism of cephalosporins containing the NMTT (cefamandole, cefmenoxime, cefoperazone, cefotetan, and moxalactam) or the N-methylthiadiazole (NMTD) (cefazolin) side chain in potentiating the development of hypoprothrombinemia (9)(10)(11)(12)15 NMTT production was greater for moxalactam than for cefotetan (18). However, comparative information in vivo is lacking.…”

mentioning

confidence: 99%

“…Several theories have been evoked to explain the mechanism of cephalosporins containing the NMTT (cefamandole, cefmenoxime, cefoperazone, cefotetan, and moxalactam) or the N-methylthiadiazole (NMTD) (cefazolin) side chain in potentiating the development of hypoprothrombinemia (9)(10)(11)(12)15). The current theory of the development of hypoprothrombinemia links this effect to an NMTT-or NMTDrelated alteration in vitamin K metabolism, as documented by an accumulation of vitamin K 2,3-epoxide (4,11).…”

mentioning

confidence: 99%

“…The current theory of the development of hypoprothrombinemia links this effect to an NMTT-or NMTDrelated alteration in vitamin K metabolism, as documented by an accumulation of vitamin K 2,3-epoxide (4,11). It is theorized that the NMTT and NMTD side chains are cleaved from the parent cephalosporins and that the free NMTT and NMTD side chains or their metabolites inhibit vitamin K epoxide reductase, similar to the inhibition seen with oral anticoagulants (15).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan

Welage

Hejmanowski

Wilton

et al. 1989

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The N-methylthiotetrazole side chain (NMTT) that is present on several cephalosporins has been implicated in the development of antibiotic-associated hypoprothrombinemia. A randomized three-way crossover trial was conducted to compare the release of the NMTT side chain from three NMTT-containing antibiotics. Single 2-g doses of moxalactam, cefoperazone, and cefotetan were given, followed by serial blood and urine sampling. The concentrations of the parent compound and the NMTT side chain in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. Peak NMTT concentrations ranged from 0.42 to 16.50 ,ug/ml and were significantly higher after moxalactam administration than after cefoperazone or cefotetan administration (P < 0.01). The NMTT trough concentrations (12.5 h) ranged from nondetectable to 2.47 ,ug/ml and tended to be greater following cefoperazone administration. The amounts of NMTT administered (e.g., the amount in the reconstituted antibiotic solution) were 25.8 ± 1.4, 15.2 ± 0.9, and 22.1 ± 3.0 mg following moxalactam, cefoperazone, and cefotetan administration, respectively (P < 0.01). In contrast, urinary recoveries of NMTT were 57.4 ± 26.2, 73.6 ± 44.3, and 29.7 ± 22.9 mg following moxalactam, cefoperazone, and cefotetan, respectively. The amount of NMTT formed in vivo and excreted unchanged, as assessed by subtracting in vitro NMTT formation from NMTT urinary recovery, was significantly higher after cefoperazone than after moxalactam or cefotetan administration (P < 0.05). The discrepancy between in vitro NMTT production (moxalactam > cefotetan > cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone > moxalactam > cefotetan) demonstrated that the in vivo production of NMTT is dependent on the disposition of the parent cephalosporin.Hypoprothrombinemia is a well-recognized complication of antibiotic therapy. Both patient risk factors and the antimicrobial agent are determinants of the prevalence of this event (3, 12, 13). Malnourished or debilitated patients receiving an antibiotic containing the N-methylthiotetrazole (NMTT) side chain appear to be at greatest risk (3,10,12,13).Several theories have been evoked to explain the mechanism of cephalosporins containing the NMTT (cefamandole, cefmenoxime, cefoperazone, cefotetan, and moxalactam) or the N-methylthiadiazole (NMTD) (cefazolin) side chain in potentiating the development of hypoprothrombinemia (9)(10)(11)(12)15 NMTT production was greater for moxalactam than for cefotetan (18). However, comparative information in vivo is lacking. As judged by the unique molecular structure and the pharmacokinetics of each of the parent compounds, the agents may be expected to yield different rates of NMTT liberation in vivo. If a variance in NMTT production exists among the agents in vivo, this may influence the relative incidence of hypoprothrombinemia among the agents.This randomized three-way crossover trial was undertaken to examine the pharmacokinetics of NMTT in hea...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Several theories have been evoked to explain the mechanism of cephalosporins containing the NMTT (cefamandole, cefmenoxime, cefoperazone, cefotetan, and moxalactam) or the N-methylthiadiazole (NMTD) (cefazolin) side chain in potentiating the development of hypoprothrombinemia (9)(10)(11)(12)15). The current theory of the development of hypoprothrombinemia links this effect to an NMTT-or NMTDrelated alteration in vitamin K metabolism, as documented by an accumulation of vitamin K 2,3-epoxide (4,11).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan

Welage

Hejmanowski

Wilton

et al. 1989

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

Mechanism of the abnormal vitamin k-dependent γ-carboxylation process in human hepatocellular carcinomas

Huisse

Leclercq

Belghiti

et al. 1994

Cancer

View full text Add to dashboard Cite

Background. An important marker for hepatocellular carcinoma is the presence of des‐γ‐carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown. Methods. Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des‐γ‐carboxy prothrombin. The enzymatic activity of y‐carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe‐Leu‐Glu‐Glu‐Leu (FLEEI.) were measured in eight tumors. The γ‐carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K, K, epoxide, and menaquinones 4‐10) in 10 tumors was investigated by high performance liquid chromatography. Results. Concentrations of menaquinones 4‐10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased γ‐carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low y‐carboxylase activity, associated with low mRNA expression in two, whereas two others had high γ carboxylase activity and mRNA expression. The concentration of FLEEL at half‐maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of γ‐carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II). Conclusions. Tumor vitamin K content has a critical role in the synthesis of des‐γ‐carboxy prothrombin. Furthermore, the γ‐carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in γ‐carboxylase gene expression could take a part in the secretion of des‐γ‐carboxy prothrombin, but this mechanism is not predominant.

show abstract

UDP‐Glucuronosyltransferases to Zn alpha‐2‐Glycoprotein

Haeberli¹

1998

Human Protein Data

View full text Add to dashboard Cite

Recent advances in hepatic vitamin k metabolism and function

Cited by 61 publications

References 126 publications

Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan

Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan

Mechanism of the abnormal vitamin k-dependent γ-carboxylation process in human hepatocellular carcinomas

UDP‐Glucuronosyltransferases to Zn alpha‐2‐Glycoprotein

Contact Info

Product

Resources

About