Hepatoprotection by dimethyl sulfoxide II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury
Rc. Lind et Aj. Gandolfi, Hepatoprotection by dimethyl sulfoxide II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury, EXP TOX PAT, 51(6), 1999, pp. 537-543
Dimethyl sulfoxide (DMSO) has previously been shown to attenuate chloroform
(CHCl3) and bromobenzene (BB) induced hepatotoxicity in the rat when a dos
e of 2.0 ml/kg is given 24 hr after the toxicants. However, the optimal dos
e of DMSO and the latest time at which DMSO can be administered and still p
rovide effective protection have not been determined. In order to determine
the latest time at which DMSO can interrupt the development of necrosis, m
ale Sprague Dawley rats received either 0.75 ml/kg CHCl3 or 0.5 ml/kg BB, 2
0% in corn oil, po, followed by single dose of 2 ml/kg DMSO, 50% in saline,
ip, at 24, 26, 28 or 30 hr later. Positive control groups received either
CHCl3 or BB and then 4.0 ml/kg saline, ip, 24 hr later. All of the animals
were then killed 48 hr after toxicant dosing. The extent of liver injury pr
esent when DMSO was administered was examined by killing animals at 24, 26,
28 or 30 hr after toxicant dosing. The optimal dose of DMSO for providing
protection was estimated by administering either 0, 1.0, 2.0, 3.0 or 4.0 ml
/kg DMSO at 24 hr after toxicant dosing and then killing the animals at 48
hr. Delaying DMSO administration to times later than 24 hr after toxicant d
osing led to a loss of protection as indicated by both plasma ALT activity
and the light microscopic appearance of liver tissue. The distinctive liver
lesions present at 24 hr after CHCl3 or BB dosing rapidly expanded from be
ing limited around central veins to bridging between centrilobular areas in
only a few hours. This was accompanied by large increases in plasma ALT. W
ith both toxicants, doses of DMSO greater than 2 ml/kg did not enhance its
protective action while the lower dose of 1 ml/kg DMSO was not as effective
. The loss of DMSO's antidotal action when given at times later than 24 hr
after the toxicants indicates irreversible changes were underway as the cen
trilobular lesions progressed from being limited to more bridging in nature
. Hopefully, further elucidation of the mechanism(s) by which DMSO interrup
ts the rapid progression of injury will both help to understand the steps i
nvolved in lesion development and provide insights into therapeutic interve
ntions for drug and chemical induced hepatitis.