Regulation of drugs metabolizing enzymes and transporters in mouse liber by primaquine

Malaria is one of the greatest of all infectious diseases, afflicting
more than 500 million people and causing around 2 million
deaths each year.
Although many classes of drugs have been used in the treatment
and prophylaxis of malaria, therapeutic failure is an
increasingly important problem either through parasite resistance
or variability in the host’s metabolism.
Drug metabolizing enzymes (mainly Cytochromes P450) and
transporters are often involved in therapeutic efficacy as well as
in clinically significant drug-drug interactions. An additional
source of variability is the regulation of those genes, which is
mediated by a group of nuclear receptors.
Although the genes involved in mammalian drug metabolism
and transport have been object of many studies, their response to
antimalarial drugs is poorly understood.
In this study we evaluated the effect of antimalarial drugs in
the hepatic expression levels of these genes using a rodent
malaria model. Expression patterns were evaluated by RT-PCR
in three strains of mice infected with Plasmodium chabaudi and
subject to a treatment with primaquine. The analysed genes
included Cytochromes P450 (from families Cyp1, Cyp2 and
Cyp3), ABC transporters (abcb1) and nuclear receptors (PXR
and CAR).
The observed changes in gene expression triggered by primaquine
exposure may be relevant for the understanding of the mechanisms
underlying drug failure and drug-drug interactions, two
of the most serious problems in malaria therapeutics.