Like many
polycyclic aromatic hydrocarbons in the environment, >30% of
benzo(a)pyrene (BP), an environmental
carcinogen and
teratogen, is eliminated by glucuronidation, which competes with a toxifying pathway involving
cytochrome P-450-catalyzed bioactivation of BP to a carcinogenic reactive intermediate, BP-7,8-diol-9,10-oxide. Genetic deficiencies in
bilirubin UDP-glucuronosyltransferase (GT) occur in >5% of the population (
Gilbert's disease,
Crigler-Najjar syndromes), and this could predispose such people to the toxic effects of
polycyclic aromatic hydrocarbons and other environmental chemicals that are eliminated substantially by glucuronidation. This hypothesis was evaluated in vitro and in vivo in homozygous Gunn and RHA rats, both of which are genetically deficient in GT. [7,10-14C]BP was incubated with rat liver microsomes,
NADPH and
uridine diphosphate-glucuronic acid. BP and its metabolites, including its
glucuronide conjugates, were measured by high performance liquid chromatography with a
radioisotope detector, and the covalent binding of BP to microsomal
protein was measured by liquid scintillation counting. Compared with Wistar (Gunn) controls and RHA homozygous normal controls, microsomes from homozygous GT-deficient Gunn and RHA rats demonstrated 18.5 to 48.5% lower production of the
glucuronide conjugate, with 2 to 3-fold greater covalent binding of BP (P < .05). Elevated BP covalent binding correlated with reduced glucuronidation in both Gunn (r = -0.705, P = .003) and RHA rats (r = 0.824, P = .001). In vivo, the covalent binding of [G-3H]BP to hepatic
DNA and microsomal
protein was enhanced 2-fold and 1.5-fold, respectively, in homozygous RHA GT-deficient rats, compared with RHA GT-normal controls (P < .05)(ABSTRACT TRUNCATED AT 250 WORDS)