Biomedical subjects

Lawrence C Mohr

Publications and source records attributed to Lawrence C Mohr.

3 recordsLinked to original sources

PubMed2006

Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.

BACKGROUND: Trichloroethylene (TCE) is a suspected human carcinogen and a common groundwater contaminant. Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH is metabolized to the hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenase (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. METHODS: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metabolism and ALDH/ADH genotype. Thirteen human hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. RESULTS: There was large interindividual variation in the Vmax values for both TCOH and TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent. Despite the large variation in Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. CONCLUSIONS: These data support the use of cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assessment models. The data are discussed with regard to cellular factors, other than genotype, that may contribute to the observed variability in metabolism of CH in human liver.

Adult↗

PubMed2004

Hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a granulomatous, inflammatory disease of the lungs caused by the inhalation of antigenic organic particles or fumes. The disease may present as an acute, subacute, or chronic illness. Episodes of acute and subacute HP usually resolve following cessation of antigen exposure. Chronic HP may be progressive, irreversible, and result in debilitating fibrotic lung disease. This review discusses current concepts regarding the diagnosis, pathogenesis, and treatment of HP. RECENT FINDINGS: The pathogenesis of HP involves both type III and type IV hypersensitivity reactions that are mediated by immune complexes and Th1 T cells, respectively. Proinflammatory cytokines and chemokines activate alveolar macrophages, cause an influx of CD8+ lymphocytes into the lungs, facilitate granuloma formation, and promote the development of pulmonary fibrosis. IFN-gamma is essential for the development of HP and IL-10 appears to modulate the severity of disease. TNF-alpha and TGF-beta have been implicated in development of the pulmonary fibrosis that is seen in chronic HP. It has been shown that pigeon fanciers with HP have an increase in the frequency of HLA-DRB1*1305 and HLA-DQB1*0501 alleles, a decrease in the frequency of the HLA-BRB1*0802 allele, and an increased frequency of the TNF-2 (-308) polymorphism of the TNF-alpha promoter gene. SUMMARY: A careful environmental and occupational history and establishment of exposure to a known inciting antigen are key factors in making the diagnosis of HP. Serum precipitating antibodies, bronchoalveolar lavage, and lung biopsy may be helpful in making the diagnosis. Avoidance of organic antigen exposure is the most important factor in the management of HP. Corticosteroids are indicated for the treatment of severe acute and subacute HP and for chronic HP that is severe or progressive. Long-term corticosteroid therapy for the treatment of chronic HP should be considered only if objective improvement in clinical signs, pulmonary function, or radiographic abnormalities is documented.

Acute Disease↗

PubMedDate not supplied

Glutathione S-transferase M1 polymorphism and the risk of lung cancer.

Glutathione S-transferases (GSTs) are a family of enzymes that detoxify hydrophobic electrophiles, including polycyclic aromatic hydrocarbon carcinogens that have been implicated in the pathogenesis of lung cancer. The GSTM1 gene within the mu class of human GSTs has been shown to be polymorphic, with individuals who are homozygous for a null allele having the GSTM1-null genotype. Individuals with the GSTM1-null genotype are deficient in both the GSTM1 and GSTM3 isoenzymes in the lung. A number of epidemiological studies have been conducted to assess the association between the GSTM1-null genotype and the risk of lung cancer. Although there have been conflicting reports regarding this relationship, the current weight of evidence indicates that the GSTM1-null genotype is probably associated with a modest increase in the risk of lung cancer. This risk appears to be greater in African-American and Asian populations than in Caucasians. Recent investigations have shown that the GSTM1-null genotype combined with CYP1A1, NAT2, or GSTP1 polymorphisms confers a greater risk of lung cancer than the GSTM1-null genotype alone. Future investigations should focus on assessing the risk of lung cancer related to multiple combinations of genetic polymorphisms that may identify individuals who are at high risk for developing lung cancer with a greater degree of certainty than is currently possible. This could lead to new clinical strategies for counseling, risk reduction and the detection of lung at an early and potentially curable stage.

Case-Control Studies↗