Toxicology Letters, 26 (1985) 31-35 Elsevier

31

TOXLett. I418

URIC ACID LEVELS IN PLASMA AND URINE IN RATS CHRONICALLY

EXPOSED TO INORGANIC As (III) AND As(V).

(Uric acid; urine; plasma; inorganic As(II1) and As(V); chronic exposure; rats)

PEDRO JAUGE and LUZ M. DEL-RAZO

Departamento de Farmacologia y Toxicologia, Cinvestav-I. P.N., Apartado Postal 14- 740, Mtxico 14,

LXF., C. P. 07000 ~~~~~0~

(Received December 12th, 1984) (Accepted February 2nd, 1985)

SUMMARY

The effect of inorganic arsenic (III) and arsenic (V) on renal excretion and plasma levels of uric acid was examined in rats. Oral administration of 1200 pg As/kg/day for 6 weeks diminished uric acid levels in plasma by 67.1 @lo and 26.5% of control after the administration of As(III) and As(V), respectively. Renal excretion of uric acid was significantly reduced during the first 3 weeks following As (III) ad- ministation, with a subsequent increase to approach control values at the end of the treatment. When As(V) was administered, the diminution in renal excretion was significant at 6 weeks.

INTRODUCTION

Uric acid is the final metabolic product of exogenous and endogenous purines in man. It is formed by oxidation of xanthine, and this reaction is catalyzed by xan- thine oxidase. In rats, the presence of uricase transforms uric acid to allantoin; this reaction can be inhibited by oxonic acid (11.

Uric acid renal excretion can be modified by the use of drugs [2,3], dietary factors [4] and inborn errors of metabolism such as gout [5,6] and Lesch-Nyham syndrome [7]. Cadmium, beryllium and lead produce changes in the urate clearance [S-10].

Inorganic arsenic (III) is regarded as sulfhydryl (-SH) reagent, inhibiting a number of thiol-dependent enzyme systems [ 11, 121 including xanthine oxidase (EC 1.2.3.2.) [13]. In rats administered sodium arsenate (50 ppm As) in the diet for 10 weeks, no significant decrease in serum uric acid levels was observed 1141.

The purpose of this research was to investigate the effect of inorganic As(II1) and As(V) on urine and plasma uric acid levels in rats exposed chronically to arsenic.

0378-4274/85/$ 03.30 0 Elsevier Science Publishers B.V.

32

MATERIALS AND METHODS

Male Wistar rats (150-160 g) were divided into groups of 5 animals. Rats were

housed individually in stainless steel metabolism cages; lab chow and water were

available ad lib. One 24-h period of adaption was allowed before any urine collec-

tion. Subsequently, 3 control weeks were allowed before As administration. From

each group, 4 rats were chronically administered with sodium arsenite (prepared

from AszOs; 99.5% resublimed GR, E. Merck, Darmstadt, F.R.G.) and sodium

arsenate (NazHAs04.7H20, Baker, Philhsburg, U.S.A.), respectively, for 6 weeks

by oral administration with gastric catheter of a daily dosis of 1200 pg As/kg body

weight. The remaining rat was kept as control during the treatment period. After 6

weeks, blood from rats was collected into EDTA tubes. Plasma was separated by

centrifugation at 2OOOxg for 10 min. Plasma and 24-h urine samples were stored

at - 10°C if not analyzed immediately.

Urine and plasma uric acid was determined by reversed-phase HPLC, using a

Varian 8500 High Pressure Liquid Chromatograph with UV detection at 294 nm

v51. Student’s t-test was used to test differences between experimental and respective

control means. In all analyses, the level of significance chosen was P<O.O5.

RESULTS

Urinary levels of uric acid in rats chronically exposed to inorganic As(II1) and

As(V) are shown in Table I. The time course of the renal excretion of uric acid is

shown in Fig. 1. We found that pg UA/min/kg body weight represents a better ex-

TABLE I

URIC ACID LEVELS IN URINE OF RATS CHRONICALLY EXPOSED TO INORGANIC As(lII)

and As(V)

Uric acid level (pg UA/min/kg) after

1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks

Control 26.4 + 3.2 25.0+ 1.2 22.8 * 2.1 23.1k1.7 22.6+ 1.3 24.7k3.0

(N = 4)

As(III) 13.7k2.8 14.1 t4.2 13.0+3.1 16.9+4.2 20.0+2.5 18.2 * 3.5

(N = 7)

P < 0.001 < 0.001 < 0.001 < 0.025 N.S.” < 0.005

As(V) 21.9+0.9 21.8* 1.0 21.8~0.8 21.1+ 1.1 20.7-+0.7 17.5k1.7

(N = 7)

P N.S. N.S. N.S. N.S. N.S. < 0.01

a Not significant.

33

30-

9, :

: \ 20- 4 3

$

lo- //

As Admmlstration

I _

0 Control x As(l111 . As(V)

I I I I / I

0 1 2 3 4 5 6

Weeks

Fig. 1. Urinary uric acid excretion in rats chronically exposed to inorganic As(III) and As(V). Arsenic

administration: 1200 pg As/kg/day.

pression for the renal excretion of uric acid in 24-h urine samples, due to differences in urine volume and body weight.

A significant decrease in urinary uric acid excretion was observed during the first 3 weeks following As(III) administration, while excretion was increased at the end of the treatment period, reaching levels close to control. When As(V) was ad- ministered, no reduction in urinary uric acid excretion was observed before the 6th week.

In plasma, we found a significant decrease in uric acid concentrations after 6 weeks (Table II), which was greater when As(II1) was administered.

DISCUSSION

Our results confirm the effect of inorganic arsenic compounds on the renal excre- tion and plasma levels of uric acid.

Uric acid concentration in plasma samples represents 32.9% (P<O.OOl) and 73.5% (P~0.05) of control values when As(II1) and As(V), respectively, was ad-

TABLE II

URIC ACID LEVELS IN PLASMA OF RATS CHRONICALLY EXPOSED TO INORGANIC As(W)

and As(V)

Control As(III) As(V)

it SD (mg UA/lOO ml) 3.28~0.38

(N = 4)’

1.08kO.07 2.41 k 0.32

(N = 7) (N = 7)

P< 0.001 P< 0.05

34

ministered. The inhibition of the enzyme xanthine oxidase by the interaction with

As(II1) [13], may be the reason for this decrease. The in vivo reduction of inorganic

As(V) to As(II1) [16] can probably explain the effect observed following As(V)

administration.

In the case of the urinary excretion, the reduction in uric acid levels could be cor-

related with the corresponding lowering of levels in plasma, but the subsequent in-

crease after 4 weeks’ administration of As(II1) could be explained if we consider the

possibility of a renal function modification attributable to arsenic.

Other metals can produce changes in uric acid clearance [g-lo]. Cadmium is

associated with uricosuria and low plasma uric acid concentrations, beryllium and

lead with hyperuricaemia due to reduced renal excretion of urates, while arsenic has

been shown to cause low plasma concentrations and reduced renal excretion of uric

acid.

ACKNOWLEDGEMEN?

This research was supported in part by grants from Conacyt (Mexico) through the

programme ‘Arsenic toxicity on reproduction’.

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