Inhibition of NADPH-cytochrome P450 reductase by cyclophosphamide and its metabolites

Marinello, Anthony J.; Berrigan, Michael J.; Struck, Robert F.; Guengerich, F. Peter; Gurtoo, Hira L.

doi:10.1016/0006-291x(81)91759-9

Cited by 22 publications

(4 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, several functionally significant single-nucleotide polymorphisms were identified in a recent study in which CPR mutations were associated with disordered steroidogenesis (Flü ck et al, 2004). In addition, it is known that CPR activity can be inhibited by a variety of drugs and other chemical agents, such as cyclophosphamide (Marinello et al, 1981), ellipticine (Guenthner et al, 1980), and cadmium (Trakshel et al, 1986).…”

Section: Mating Groupmentioning

confidence: 99%

Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450

Wu¹,

Gu²,

Cui³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A mouse model with a hypomorphic NADPH-cytochrome P450 reductase (Cpr) gene (designated Cpr low allele) was generated and characterized in this study. The Cpr gene in these mice was disrupted by the insertion of a neo gene in intron 15, which led to 74 to 95% decreases in CPR expression in all tissues examined, including olfactory mucosa, adrenal gland, brain, testis, ovary, lung, kidney, liver, and heart. In the liver, a pattern of pericentral distribution of CPR protein was preserved in the Cpr low/low mice, despite an overall reduction in CPR expression. Genotype distribution in F2 pups indicated limited embryonic lethality associated with the Cpr low allele, a finding that confirms the role of CPR-dependent enzymes in development. Adult male homozygotes had decreased body weight and decreased heart, lung, and kidney weights, whereas homozygous Cpr low females, which had increased serum testosterone and progesterone and decreased copulatory activities, were infertile. Furthermore, adult Cpr low/low mice had decreased plasma cholesterol, and some mice developed mild centrilobular hepatic lipidosis. In addition, despite apparently compensatory increases in total microsomal cytochrome P450 content in the liver and kidney, the decreases in CPR expression were accompanied by reductions in systemic clearance of pentobarbital, as well as in hepatic microsomal metabolism of acetaminophen and testosterone. These phenotypes illustrate the potential impact of a globally decreased CPR activity in human adults, and this novel knock-in mouse model provides a unique opportunity for further explorations of the in vivo roles of CPR and CPR-dependent enzymes.

show abstract

Section: Mating Groupmentioning

confidence: 99%

Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450

Wu¹,

Gu²,

Cui³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…ALA-S could itself be a partial target for acrolein since it has been shown to contain an -SH group at its active centre and to be inhibited by the sulphydryl inhibitors N-ethylmaleimide and p-chloromercuribenzoate 37' 38. Furthermore the reaction of acrolein with available sulphydryl groups of enzymes has been described 39 41. The other possibility is that CP metabolites interact with the genetic mechanism controlling ALA-S synthesis, bearing in mind that interaction of CP metabolites with nucleic acids is well established 42 and alkylation and inhibition of synthesis of RNA and DNA in vivo seem to occur at the peak after 2448 h 43'44.…”

mentioning

confidence: 97%

Cyclophosphamide-impaired regulation of hepatic heme metabolism

et al. 1984

View full text Add to dashboard Cite

In male rats hepatic cytochromes b5 and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a 'non-cytochromal' form. Parallel to the above changes the heme metabolism showed derangement: delta-aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.

show abstract

“…In rats, cyclophosphamide pretreatment resulted in a significant decrease in adriamycin clearance (Hartman et al 1982). Cyclophosphamide had previously been demonstrated to inhibit NADPH cytochrome P-450 reductase (Marinello et al 1981) and microsomes from rats pretreated with cyclophosphamide showed a 24% reduction in this enzyme's activity accompanied by a decrease in the formation of 7-deoxyadriamycinol aglycone (Dodion et al 1984). 7-Deoxyadriamycin aglycone was not affected.…”

Section: Biotransformationmentioning

confidence: 96%

“…Marinello et al (1981) have implicated one of the end-products of cyclophosphamide metabolism, acrolein, as the active inhibitor of NADPH cytochrome P-450 reductase. Reich and Bachur (1976) studied the effects of phenobarbitone on the pharmacokinetics of adriamycin in mice.…”

Section: Biotransformationmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Commonly Used Anticancer Drugs

Balis

1986

Clinical Pharmacokinetics

View full text Add to dashboard Cite

With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example, the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids, such as probenecid, salicylates and penicillin, which compete for tubular secretion, resulting in delayed clearance of methotrexate. The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.

show abstract

Inhibition of NADPH-cytochrome P450 reductase by cyclophosphamide and its metabolites

Cited by 22 publications

References 13 publications

Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450

Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450

Cyclophosphamide-impaired regulation of hepatic heme metabolism

Pharmacokinetic Drug Interactions of Commonly Used Anticancer Drugs

Contact Info

Product

Resources

About