Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1992-11-20
pubmed:abstractText
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)
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
263
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
334-42
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1992
pubmed:articleTitle
In vitro and in vivo biotransformation and covalent binding of benzo(a)pyrene in Gunn and RHA rats with a genetic deficiency in bilirubin uridine diphosphate-glucuronosyltransferase.
pubmed:affiliation
Department of Pharmacology, University of Toronto, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't