Plasmodium berghei (ANKA): Infection induces CYP2A5 and 2E1 while depressing other CYP isoforms in the mouse liver

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Abstract

It has been reported that malaria infection impairs hepatic drug clearance and causes a down-regulation of CYP-mediated monooxygenase activities in rodents and humans. In the present study, we investigated the effects of Plasmodium berghei infection on the activity of liver monooxygenases in female DBA/2 and C57BL/6 mice. In both mouse strains, P. berghei infection decreased activities mediated by CYP1A (EROD: DBA/2 65.3%, C57BL/6 44.7%) and 2B (BROD: DBA/2 64.3%, C57BL/6 49.8%) subfamily isoforms and increased activities mediated by 2A5 (COH: DBA/2 182.4%, C57BL/6 148.5%) and 2E1 (PNPH: DBA/2 177.8%, C57BL/6 128.5%) isoforms as compared to non-infected controls. Since malaria infection also produced an increase in ALT (273.1%) and AST (354.1%) activities in the blood serum, our findings are consistent with the view that CYP2A5 activity is induced by liver injury. An almost generalized depression of CYP-mediated activities has been found with numerous infections and inflammatory stimuli but an induction of CYP2A5 had been previously noted only in some viral hepatitis and trematode (liver fluke) infections.

Introduction

Several clinical and experimental studies have demonstrated that malaria infection down-modulates the expression and activity of CYPs thereby decreasing the hepatic metabolism of drugs and other xenobiotic compounds in humans and rodents. In 1970, McCarthy and coworkers reported that infection of rats with Plasmodium berghei increased hexobarbital sleeping time and reduced hepatic metabolism of ethylmorphine, aniline and p-nitroanisole. Further studies found that infection with P. berghei decreased total-CYP content and monooxygenase activities in rat liver microsomes (Kokwaro et al., 1993, Uhl et al., 1999) as well as the clearance of xenobiotics such as artheether (Leo et al., 1997), ethoxyresorufin (Glazier et al., 1994), antipyrine (Mansor et al., 1991a), paracetamol (Mansor et al., 1991b), and phenacetin (Kokwaro et al., 1993). Malaria infection was found to reduce total-CYP content and monooxygenase activities in mouse liver as well (Alvares et al., 1984, Srivastava and Pandey, 2000, Srivastava et al., 1991, Srivastava et al., 1997).

Data from clinical pharmacokinetic studies have also been consistent with the hypothesis that malaria infection depresses CYP-mediated drug metabolism. It was reported, for instance, that clearances of quinine, antipyrine and caffeine were reduced in patients with acute Plasmodium falciparum malaria (Akinyinka et al., 2000, Pukrittayakamee et al., 1997).

Contrasting to the foregoing findings suggesting that malaria causes a generalized depression of liver CYP activities, Uhl et al. (1999) reported that CYP2E1 activity remains unaltered in liver microsomes of P. berghei-infected rats. As far as the authors are aware, however, there has been no report of induction of liver monooxygenases by malaria infection so far.

In the present study, we investigated the effects of P. berghei infection on mouse liver monooxygenase activities mediated by CYP2A5 (COH) and 2E1 (PNPH) as well as by isoforms belonging to subfamilies CYP1A (EROD) and 2B (BROD). CYP1A1/2 and 2E1 are involved in the metabolic activation of a number of xenobiotic compounds including many chemical carcinogens (Ioannides and Lewis, 2004). Isoenzymes belonging to CY2B subfamily also take part in the activation of toxicants as well as in the metabolic clearance of artemisinin, an important antimalarial drug (Simonsson et al., 2003). It is of note that CYP2A5, a murine isoform orthologous to human CYP2A6, plays an essential role in the activation of various hepatotoxins and carcinogens, including nitrosamines, and apparently has a unique mechanism of regulation (Gilmore et al., 2003). Contrasting to most CYP isoforms, CYP2A5 is induced in some infectious diseases such as viral hepatitis and liver fluke infection (Kirby et al., 1994a, Kirby et al., 1994b).

Section snippets

Animals

Female C57BL/6 and DBA/2 mice, 7–10 weeks old, from the Oswaldo Cruz Foundation (FIOCRUZ) breeding stock were used. The animals were housed in standard plastic cages with stainless steel coverlids and wood shavings as bedding. Room temperature (23 ± 2 °C), air relative humidity (approx. 70%) and light/dark cycle (lights on from 8:00 am to 8:00 pm) were controlled in the animal facilities. Filtered tap water and a commercial diet for rats and mice (Nuvital CR1, Nuvilab®, Curitiba, PR, Brazil) were

Results and discussion

DBA/2 and C57BL/6 mice inoculated with 106 P. berghei-parasitized red blood cells consistently achieved high rates of parasitemia between days 12–20 (DBA/2) and 9–21 (C57BL/6) after inoculation when the animals were killed for preparation of liver microsomal fraction. The marked rise in parasitemia rate after postinoculation day 9 was accompanied by clinical signs such as weight loss, hypoactivity, piloerection, and tachypnea. As shown in Table 1, on the day of sacrifice, infected mice from

Acknowledgments

FJRP is the recipient of a fellowship from the Brazilian National Research Council (CNPq) and the research project is supported by grants from CNPq, FAPERJ and PAPES-FIOCRUZ. We are thankful to Dr. Leonardo Carvalho and to Prof. Claudio Tadeu Daniel Ribeiro from the Laboratory of Research on Malaria of the Oswaldo Cruz Institute—FIOCRUZ for providing the P. berghei (ANKA) parasites used in the study.

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