Cytochrome P{sub 450}-dependent toxic effects of primaquine on human erythrocytes

Journal Article · Sun Nov 15 00:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.07.012· OSTI ID:21344784

Ganesan, Shobana ^[1]; Sahu, Rajnish; Tripathi, Lalit M; Walker, Larry A ^[1]

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1. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University MS 38677 (United States)

Primaquine, an 8-aminoquinoline, is the drug of choice for radical cure of relapsing malaria. Use of primaquine is limited due to its hemotoxicity, particularly in populations with glucose-6-phosphate dehydrogenase deficiency [G6PD(-)]. Biotransformation appears to be central to the anti-infective and hematological toxicities of primaquine, but the mechanisms are still not well understood. Metabolic studies with primaquine have been hampered due to the reactive nature of potential hemotoxic metabolites. An in vitro metabolism-linked hemotoxicity assay has been developed. Co-incubation of the drug with normal or G6PD(-) erythrocytes, microsomes or recombinant cytochrome P{sub 450} (CYP) isoforms has allowed in situ generation of potential hemotoxic metabolite(s), which interact with the erythrocytes to generate hemotoxicity. Methemoglobin formation, real-time generation of reactive oxygen intermediates (ROIs) and depletion of reactive thiols were monitored as multiple biochemical end points for hemotoxicity. Primaquine alone did not produce any hemotoxicity, while a robust increase was observed in methemoglobin formation and generation of ROIs by primaquine in the presence of human or mouse liver microsomes. Multiple CYP isoforms (CYP2E1, CYP2B6, CYP1A2, CYP2D6 and CYP3A4) variably contributed to the hemotoxicity of primaquine. This was further confirmed by significant inhibition of primaquine hemotoxicity by the selective CYP inhibitors, namely thiotepa (CYP2B6), fluoxetine (CYP2D6) and troleandomycin (CYP3A4). Primaquine caused similar methemoglobin formation in G6PD(-) and normal human erythrocytes. However, G6PD(-) erythrocytes suffered higher oxidative stress and depletion of thiols than normal erythrocytes due to primaquine toxicity. The results provide significant insights regarding CYP isoforms contributing to hemotoxicity and may be useful in controlling toxicity of primaquine to increase its therapeutic utility.

• OSTI ID: 21344784
• Journal Information: Toxicology and Applied Pharmacology, Vol. 241, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.07.012; PII: S0041-008X(09)00293-2; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINES
CYTOCHROMES
ERYTHROCYTES
GLUTATHIONE
IN VITRO
LIVER
MALARIA
MEN
METABOLITES
METHEMOGLOBIN
MICE
MICROSOMES
OXIDATION
QUINOLINES
STRESSES
TOXICITY
ANIMALS
AROMATICS
AZAARENES
AZINES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
DISEASES
DRUGS
GLANDS
GLOBINS
HEMOGLOBIN
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
INFECTIOUS DISEASES
MALES
MAMMALS
MAN
MATERIALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PARASITIC DISEASES
PEPTIDES
PIGMENTS
POLYPEPTIDES
PORPHYRINS
PRIMATES
PROTEINS
PYRIDINES
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RIBOSOMES
RODENTS
VERTEBRATES