Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental toxicants derived from sources that include cigarette smoke, petroleum distillation, gas-and diesel-engine exhaust, and charcoal-grilled food. The gastrointestinal tract is the principal route of PAH exposures, even when inhaled. The most thoroughly studied prototype of PAHs is benzo[a]pyrene (BaP), well known to be toxic, mutagenic, and carcinogenic in various tissues and cell types. This lab has previously shown that Cyp1a1(Ϫ/Ϫ) global knockout mice treated by oral administration of BaP die at 28 to 32 days with immunosuppression, whereas wild-type mice remain healthy for 1 year on high BaP doses (125 mg/kg/day). Thus, for oral BaP, CYP1A1 is more important in detoxication than in metabolic activation. After several days of oral BaP, we found surprisingly low CYP1A1 levels in liver, compared with that in small intestine; we postulated that this finding might reflect efficient detoxication of oral BaP in proximal small intestine such that significant amounts of the inducer BaP no longer reach the liver. In the present study, many parameters were therefore compared in wild-type, Cyp1a1(Ϫ/Ϫ) global knockout, intestinal epithelial cell-specific Cyp1a1 knockout, and hepatocyte-specific Cyp1a1 knockout mice as a function of long-term oral exposure to BaP. The peak of CYP1A1 (mRNA, protein) expression in liver occurred at 12 h, whereas highly induced CYP1A1 in small intestine persisted throughout the 30-day experiment. Hepatocyte-specific Cyp1a1 knockout mice remained as healthy as wild-type mice; intestinal epithelial cell-specific Cyp1a1 knockout mice behaved like Cyp1a1(Ϫ/Ϫ) mice, dying with immunosuppression ϳ30 days on oral BaP. We conclude that small intestine CYP1A1, and not liver CYP1A1, is critically important in oral BaP detoxication.

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1 Knockout Mouse Lines as a Paradigm

“…2C, left); this leads to severely impaired clearance of BaP total body burden, large amounts of BaP reaching distal tissues such as bone marrow and immune tissue, and resultant CYP1B1-mediated bone marrow toxicity, immunosuppression, and death. These two conditional knockout mouse models were supported with further pharmacokinetics parameters, blood and plasma enzyme measurements, and histology (Shi et al, 2010a). It can be unequivocally concluded that GI tractinducible CYP1A1, but not CYP1B1 or CYP1A2, can detoxify enormous amounts of oral BaP.…”

“…Answers to these questions can only be resolved by using conditional Cyp1a1(2/2) knockout lines. The Alb.Cre.Cyp1a1(f/f) line was thus created in which CYP1A1 is specifically ablated from albumin-expressing hepatocytes, whereas CYP1A1 is present and inducible in the rest of the animal, including the GI tract (Shi et al, 2010a). The Vil.Cre.Cyp1a1(f/f) line was also developed in which CYP1A1 function is deleted from villin-expressing epithelial cells of the GI tract (also renal epithelial cells, which are of no consequence in these experiments), meaning that CYP1A1 is present and inducible in the rest of the animal including the hepatocytes (Shi et al, 2010a).…”

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

“…Uno et al (2004) analyzed the clearance of BaP in the blood of mice following gavage exposure, and showed that the levels of BaP in the blood increased until 45 minutes post-exposure and were undetectable by four hours post-exposure. Oral BaP is known to be detoxified in the small intestine very efficiently (Uno et al 2006 and Nebert et al, 2013a), where Cyp1a1 gene expression persists for over 30 days post-exposure (Shi et al, 2010a), implying that the major contributor to BaP detoxication occurs in the small intestine. While the small intestine plays a major role in detoxifying BaP, BaP distribution to distal organs following oral exposure also occurs.…”

Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing Enzyme

“…However, metabolism during absorption across the intestinal wall also influences the bioavailability of orally administered compounds (van de Kerkhof et al, 2007). For instance, it has recently been reported that intestinal CYP1A1, but not hepatic CYP1A1, is the key enzyme in oral benzo[a]pyrene detoxification (Shi et al, 2010). Given that ethanol is usually administered via the oral route, ALDH1B1 in the intestinal wall may play an important role in the initial metabolism of ethanol or of orally ingested aldehydes, whereas ALDHs associated with the liver would be anticipated to process any aldehydes in the hepatic portal vein or in the systemic circulation.…”