Ab. Lindstrom et al., FORMATION OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF BENZENE OXIDE IN MOUSE, RAT, AND HUMAN BLOOD, Chemical research in toxicology, 11(4), 1998, pp. 302-310
Little is known about the formation and disposition of benzene oxide (
BO), the initial metabolite arising from oxidation of benzene by cytoc
hrome P450. In this study, reactions of BO with hemoglobin (Hb) and al
bumin (Alb) were investigated in blood from B6C3F(1) mice, F344 rats,
and humans in vitro. The estimated half-lives of BO in blood were 6.6
min (mice), 7.9 min (rats), and 7.2 min (humans). The following second
-order rate constants were estimated for reactions between BO and cyst
einyl residues of Hb and Alb [in units of L (g of Hb- or Alb-h)(-1)]:
mouse Hb = 1.16 x 10(-4), rat Hb = 15.4 x 10(-4), human Hb = 0.177 x 1
0(-4), mouse Alb = 2.68 x 10(-4), rat Alb = 4.96 x 10(-4), and human A
lb = 5.19 x 10(-4). These rate constants were used with BO-adduct meas
urements to assess the systemic doses of BO arising from benzene in vi
vo in published animal and human studies. Among rats receiving a singl
e gavage dose of 400 mg of benzene/kg of body weight, the BO dose of 2
.62 x 10(3) nM BO-h, predicted from Alb adducts, was quite similar to
the reported AUC(0-infinity) = 1.09 x 10(3) nM BO-h of BO in blood. In
terestingly, assays of Hb adducts in the same rats predicted a much hi
gher dose of 14.7 x 10(3) nM BO-h, suggesting possible in situ generat
ion of adducts within the erythrocyte. Doses of BO predicted from Alb
adducts were similar in workers exposed to benzene [13.3 nM BO-h (mg o
f benzene/kg of body weight)(-1)] and in rats following a single gavag
e dose of benzene [8.42 nM BO-h (mg of benzene/kg of body weight)(-1)]
. Additional experiments indicated that crude isolates of Hb and Alb h
ad significantly higher levels of BO adducts than dialyzed proteins, s
uggesting that conjugates of low-molecular-weight species were abundan
t in these isolates.