Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo

doi:10.1016/0166-6851(80)90050-X

Molecular and Biochemical Parasitology

Volume 1, Issue 6, 1980, Pages 315-333

https://doi.org/10.1016/0166-6851(80)90050-X Get rights and content

Abstract

After a single intravenous injection of suramin the rate of removal of the drug from the plasma into other tissue compartments of the rat is independent of intial concentration. The data can be fitted to the sum of two exponential functions, consistent with a two-compartment, open model system.

Trypanosomes take up only small amounts of suramin in vivo and do not actively concentrate the drug within the cell. Uptake is apparently by non-saturable process that decreases with time and is dependent on the amount of suramin already taken up. Once within the cell, suramin progressively inhibits respiration and glycolysis, such that, for a given exposure in vivo, inhibition of oxygen consumption is proportional to the total amount of suramin absorbed. It can be calculated that only a fraction (4–9%) of this total is required to inhibit respiration to the extend found in broken cell preparations. The combined inhibition of two key enzymes in glycolysis — the sn-glycerol-3-phosphate oxidase (EC unassigned) and the glycerol-3-phosphate dehydrogenase (NAD⁺) (sn-glycerol-3-phosphate: NAD⁺ 2-oxidoreductase, EC 1.1.1.8) — are sufficient to account for the differential inhibition of glucose and oxygen consumption and of pyruvate production, together with the small, but significant, production of glycerol. Even at the highest dose of suramin tolerated by the rat, trypanosomes continue to increase exponentially in the bloodstream for at least 6 h. The mean doubling time is increased from 4.6 h to a maximum of about 12.5 h in rats treated with doses of suramin in the range 25–150 mg/kg. In the light of these and other findings, it is concluded that part of the trypanocidal action of suramin results from the inhibition of ATP production by glycolysis.

References (46)

F. Hawking
Suramin: with special reference to onchocerciasis
Adv. Pharmacol. Chemother.
(1978)
G.C. Hill et al.
Effect of trypanocidal drugs on terminal respiration of Crithidia fasciculata
Exp. Parasitol.
(1968)
A.H. Fairlamb et al.
Trypanosoma brucei: suramin and other trypanocidal compounds' effects on sn-glycerol-3-phosphate oxidase
Exp. Parasitol.
(1977)
J.J. Jaffe et al.
Comparative properties of schistosomal and filarial dihydrofolate reductases
Biochem. Pharmacol.
(1972)
P.L. Chello et al.
Comparative properties of trypanosomal and mammalian thymidine kinases
Comp. Biochem. Physiol.
(1972)
O.H. Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
A.H. Fairlamb et al.
An improved method for the estimation of suramin in plasma and trypanosome samples
Mol. Biochem. Parasitol.
(1980)
A.H. Fairlamb et al.
The isolation and characterisation of particulate sn-glycerol-3-phosphate oxidase from Trypanosoma brucei
Int. J. Biochem.
(1977)
G.L. Atkins
A versatile digital computer programme for non-linear regression analysis
Biochim. Biophys. Acta
(1971)
F.R. Opperdoes et al.
Localisation of nine glycolytic enzymes in a microbody-like organelle in Trypanosoma brucei: the glycosome
FEBS. Lett.
(1977)

W.E. Muller et al.

Spectroscopic studies on the complex formation of suramin with bovine and human serum albumin

Biochim. Biophys. Acta

(1976)

D. Damper et al.

Pentamidine transport in Trypanosma brucei — kinetics and specificity

Biochem. Pharmacol.

(1976)

F.R. Opperdoes et al.

The potential use of inhibitors of glycerol-3-phosphate oxidase for chemotherapy of African trypanosomiasis

FEBS Lett.

(1976)

F.R. Opperdoes et al.

Trypanosoma brucei: an evaluation of salicylhydroxamic acid as a trypanocidal drug

Exp. Parasitol.

(1976)

F.I.C. Apted

Treatment of human trypanosomiases

J. Williamson

Review of chemotherapeutic and chemoprophylactic agents

E.A. Steck

J.G. Olenick

Suramin

C.J. Bacchi et al.

O₂-Polarographic studies on soluble and mitochondrial enzymes of Crithidia fasciculata; glycerophosphate enzymes

J. Protozool.

(1968)

G.C. Hill et al.

In vitro transcription of kinetoplast and nuclear DNA in Kinetoplastida

J. Protozool.

(1974)

B. Goldberg et al.

Inhibition by several standard antiprotozaal drugs of growth and O₂ uptake of cells and particulate preparations of a Leptomonas

J. Protozool.

(1974)

M. Gottlieb et al.

Crithidia as a model organism?

J Parasitol.

(1972)

A.H. Fairlamb et al.

Studies on glycerophosphate oxidase of Trypanosoma brucei

Trans. R. Soc. Trop. Med. Hyg.

(1975)

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^∗: Present address: Department of Medical Protozoology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, England.

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Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo

Abstract

Adv. Pharmacol. Chemother.

Exp. Parasitol.

Exp. Parasitol.

Biochem. Pharmacol.

Comp. Biochem. Physiol.

J. Biol. Chem.

Mol. Biochem. Parasitol.

Int. J. Biochem.

Biochim. Biophys. Acta

FEBS. Lett.

Biochim. Biophys. Acta

Biochem. Pharmacol.

FEBS Lett.

Exp. Parasitol.

Treatment of human trypanosomiases

Review of chemotherapeutic and chemoprophylactic agents

Suramin

O2-Polarographic studies on soluble and mitochondrial enzymes of Crithidia fasciculata; glycerophosphate enzymes

J. Protozool.

In vitro transcription of kinetoplast and nuclear DNA in Kinetoplastida

J. Protozool.

Inhibition by several standard antiprotozaal drugs of growth and O2 uptake of cells and particulate preparations of a Leptomonas

J. Protozool.

Crithidia as a model organism?

J Parasitol.

Studies on glycerophosphate oxidase of Trypanosoma brucei

Trans. R. Soc. Trop. Med. Hyg.

O₂-Polarographic studies on soluble and mitochondrial enzymes of Crithidia fasciculata; glycerophosphate enzymes

Inhibition by several standard antiprotozaal drugs of growth and O₂ uptake of cells and particulate preparations of a Leptomonas